DE3805801A1 - ANTI-HYPERCHOLESTERINAEMICALLY ACTIVE TETRAZOLE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND PHARMACEUTICAL AGENTS - Google Patents

Description

The invention relates to new tetrazole compounds which effective inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. These connections are therefore for the treatment or prevention of hypercholesterolemia, Hyperlipoproteinemia and arteriosclerosis are useful. The The invention also relates to a method for producing the Tetrazole compounds and intermediates for manufacturing of the compounds of the invention.

The natural fermentation products Compactin (R = H), the by A. Endo et al, in the Journal of Antibiotics, 29, 1346-1348 (1976) was described, and mevinolin (R = CH₃) by A. W. Alberts et al in J. Proc. Natl. Acad. Sci. USA, 77, 3957 (1980) are very effective anti hypercholerestinemic agents that promote cholesterol biosynthesis limit by inhibiting the enzyme HMG-CoA reductase, the speed limiting enzyme and natural factor of cholesterogenic regulation in mammals, including humans. Compactin (R = H) and Mevinolin (R = CH₃; also known as Lovastatin) have the following structure:

Numerous structurally related synthetic compounds, which are useful for the treatment of hypercholesterolemia, have also been used in patent and other publications described. The most relevant state of the art is in explains the following:

The US-PS 41 98 425 describes new mevalonolactone derivatives, which are useful for the treatment of hyperlipidemia and which have the general formula:

where A is a direct link, a methylene, ethylene, Trimethylene or vinylene group means and R³, R⁴ and R⁵ stand for different substituents.

EP-A-0 0 24 348 describes new hypocholesterolemic and hypolipemic compounds of the general formula:

wherein A is H or methyl; E a direct link, -CH₂-, - (CH₂) ₂-, - (CH₂) ₃- or -CH = CH-; R¹, R² and R³ each represent different substituents, and the corresponding dihydroxy acids by hydrolytic Opening of the lactone ring can be obtained.

The US-PS 43 75 475 describes essentially compounds the same structure and corresponds to the mentioned EP-A- 00 24 348.

EP-A-68 038 describes the separated trans enantiomer, a process for its manufacture and a pharmaceutical Medium, this connection has the following structure:

The corresponding dihydroxy acid as well as the pharmaceutical compatible salts thereof are also described.

International patent application WO 84/02131 describes Analogs of mevalonolactone of the formula:

wherein
one of
Leftovers R
and R⁰for is and the other is primary or secondary C _1-6 alkyl, C _3-6 cycloalkyl or phenyl- (CH₂) _n ; X is - (CH₂) _n or -CH = CH-; n stands for 0, 1, 2 or 3, Z for stands and R⁴, R⁵,
R ^5a and R⁶ represent different substituents.

International patent application WO 84/02903 describes Mevalonolactone analogues of the formulas:

wherein
X for

stands;
n = 0, 1, 2 or 3 and both q 's are 0 or one is 0 and the other is 1, and

EP-A 1 42 146 describes oxo analogs of mevinolin Similar antihypercholesterolemic agents of the formula:

wherein E is -CH₂-CH₂-, -CH = CH- or - (CH₂) ₃-; and Z for

stands, whereby the dashed lines mean double bonds and where there are 0, 1 or 2 double bonds can.

J. Med. Chem., 28, 347-358 (1985) report G.E. Stokker et al, on the manufacture and testing of a number of 5-substituted, 3,5-dihydroxypentane carboxylic acids and their Derivatives.

In J. Med. Chem., 29, 159-169 (1986) W. W. Hoffmann et al, the manufacture and testing of a number of 7- (substituted Aryl) -3,5-dihydroxy-6-heptene (heptane) carboxylic acids and the lactone derivatives thereof. One of the preferred compounds has the formula:

In J. Med. Chem., 29, 170-181 (1986), G.E. Stokker et al synthesized a series of 7- [3,5-disub substituted (1,1'-biphenyl) -2-yl] -3,5-dihydroxy-6-heptene carboxylic acid and its lactones. Two of the preferred ones in this Compounds described in the publication have the formulas:

US Pat. No. 4,613,610 describes pyrazole analogs of mevalonolactone and their derivatives, which are used to treat Hyperlipoproteinemia and arteriosclerosis are useful and which have the general formula:

wherein X is - (CH₂) _n -, -CH = CH-, -CH = CH-CH₂- or -CH₂-CH = CH-; n represents 0, 1, 2 or 3 and R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and Z represent different substituents.

None of the publications mentioned describe or lay the Possibility of producing the compounds according to the invention Near. The compounds of the invention have a large HMG-CoA activity and differ nevertheless due to the tetrazole unit in structural terms considerably from the state of the art.

The invention relates to new compounds of the general Formula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶, tet, n and A are as defined below. These compounds are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and are useful for the treatment of hypercholesterolemia, hyperlipoproteinemia and arteriosclerosis. The invention also relates to useful intermediates, processes for their preparation and processes for the preparation of the compounds (I).

The compounds of the invention, the inhibitors of Enzyme HMG-CoA reductase and are used to treat Hyperchloesterinaemia, hyperlipoproteinemia and arteriosclerosis have the general formula (I):

wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; tetfür stands for n is an integer from 0 to 2 inclusive, for stands; R⁷ represents a hydrogen atom, a C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl group; X is -OH or = O; and R⁸ represents a hydrogen atom, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt.

The invention also relates to methods for producing the Compounds of formula (I) and intermediates for their manufacture of the compounds of formula (I).

The terms "C _1-4 alkyl", "C _1-6 alkyl" and "C _1-4 alkoxy" mean (unless stated otherwise) branched or unbranched alkyl or alkoxy groups, such as methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, t-butyl, amyl, hexyl, etc. Preferably these groups contain 1 to 4 carbon atoms, most preferably 1 or 2 carbon atoms. The term "lower alkyl" in the substituent "C _1-4 alkoxy-" (lower) alkyl means unbranched or branched alkyl groups having 1 to 4 carbon atoms and preferably 2 carbon atoms. Unless otherwise specified, the term "halogen" includes chlorine, fluorine, bromine and iodine, while the term "halide" includes the chloride, bromide and iodide anion. The term "a cation to form a non-toxic, pharmaceutically acceptable salt" includes non-toxic alkali and alkaline earth metal salts such as the sodium, potassium, calcium, magnesium salts, the ammonium salt and salts with non-toxic amines such as Trialkylamines, dibenzylamine, pyridine, N-methylmorpholine, N-methylpiperidine and other amines which are used to form carboxylic acid salts.

Unless otherwise stated, the term "hydrolyzable ester group" means an ester group which is physiologically acceptable and hydrolyzable under physiological conditions, e.g. B. C _1-6 alkyl, phenylmethyl or pivaloyloxymethyl.

The compounds of the formula (I) all have double bonds in trans configuration before, d. H. the configuration is indicated in the formulas with (E).

The compounds of the invention have one or two asymmetric carbon atoms. The invention therefore includes all enantiomeric and diastereomeric forms of the compounds of formula (I). The compounds of formula (I) which Containing two centers of asymmetry can contain four stereoisomers form which are referred to as RR, RS, SR and SS enantiomers will; the present invention encompasses all four stereoisomers. In particular, the compounds of the formula (I) which have two asymmetric carbon atoms and the hydroxy groups in the 3- and 5-positions have four Form stereoisomers which are (3R, 5S), (3S, 5R), (3R, 5R) and (3S, 5S) stereoisomers. The expression "(±) -erythro" includes a mixture of (3R, 5S) - and (3S, 5R) enantiomers and the expression "(±) threo" a mixture of the (3R, 5R) and (3S, 5S) enantiomers. The Use a single label, such as (3R, 5S) essentially a stereoisomer. The lactone forms of the compounds of formula (I) also have two asymmetrical ones 4- and 6-position carbon atoms. The received from it four stereoisomers are called (4R, 6S) -, (4S, 6R) -, (4R, 6R) - and (4S, 6S) stereoisomers. The term "trans" lactone comprises a mixture of the (4R, 6S) and (4S, 6R) enantiomers, while the term "cis" lactone is a mixture of the (4R, 6R) and (4S, 6S) enantiomers. The isomer mixtures can be done using methods known per se, for example by fractional crystallization, adsorption chromatography or other suitable separation method in which separate individual isomers. The racemates obtained can one in the usual way after the introduction of suitable salt-forming agents Separate groups into the antipodes, for example by forming a mixture of diastereomeric salts with optically active salt-forming agents, separation of the Mix in diastereomeric salts and transfer the separated Salts in the free compounds. The enantiomeric Shaping can also be done by chiral high fractionation Separate the pressure liquid chromatography columns.

If it is desired to prepare the (+) isomer of a compound of the formula (I), the synthetic (±) isomer of this compound can be separated using known methods. As an example of a separation method in this class of compounds, reference is made to US 4,375,475. Accordingly, a racemic (±) -trans lactone is separated with excess d - (+) - α- methylbenzylamine (or the corresponding 1 - (-) - α- methylbenzylamine), by separating the two diastereomeric amines obtained and, for example, by hydrolysis to the corresponding sodium salt. The salt obtained can then be converted into the corresponding acid, the corresponding ester and the corresponding lactone using customary methods. The optically active enantiomers of the compounds of formula (I) can preferably be prepared by stereoselective synthetic methods, some of which are described. The use of optically active reagents in combination with the corresponding intermediates provides the desired enantiomer of the compounds of the formula (I).

Since the compounds of formula (I) have different amounts seem to contain solvent, which mainly shown by elemental analysis includes the present Invention also the solvates of the compounds of the Formula (I). In some cases, the products seem real To be solvate while in other cases the products contain only the solvent accompanying or one Mixture of Solvat and some accompanying solvent are. Preferably the solvate is water and most preferred 1 to 3 moles of water are present as a solvate. In the The following examples are, if necessary, the Amount of solvent in the results for elemental analysis specified. The melting points are those of the solvated products unless otherwise stated.

In the compounds of formula (I), the substituents R¹, R², R³, R⁴, R⁵ and R⁶ independently of one another and preferably represent a hydrogen or halogen atom, or a C _1-4 alkyl or C _1-4 alkoxy group. R¹ and R⁴ are particularly preferably a hydrogen atom and R², R³, R⁵ and R⁶ independently of one another are a hydrogen, fluorine or chlorine atom or a methyl or methoxy group. Most preferably, R¹ and R⁴ are hydrogen and R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or fluorine or methyl or methoxy. N is preferably 0, 1 or 2 and particularly preferably 1. tet is preferably 1H-tetrazol-5-yl or 1-substituted-1H-tetrazol-5-yl. T is particularly preferably 1-methyl-1H-tetrazol-5-yl, 1-ethyl-1H-tetrazol-5-yl, 1-methylethyl-1H-tetrazol-5-yl or 1- (2-methoxyethoxy) methyl -1H-tetrazol-5-yl and most preferred for 1-methyl-1H-tetrazol-5-yl. Preferably X is -OH or = O and most preferably -OH. R⁸ is preferably a hydrogen atom or a C _1-6 alkyl group or a pharmaceutically acceptable cation. Most preferably R⁸ is a pharmaceutically acceptable cation, especially sodium or potassium.

Among the compounds of the formula (I) according to the invention, in which A contains two asymmetric carbon atoms and the Having a hydroxyl group, the erythro isomer is preferred. The (3R, 5S) isomer is particularly preferred. Among the connections of formula (I) in which A has two asymmetric carbon atoms in the lactone form is the trans isomer and particularly preferred the (4R, 6S) isomer.

The compounds of formula (I) according to the invention can by means of various methods, preferably one from a compound of the general formula (IIa) or (IIb) runs out:

wherein R¹ and R⁴ each independently represent a hydrogen or halogen atom or a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³, R⁵ and R⁶ each independently represent a hydrogen or halogen atom or a C _{1 -C} 4 -alkyl or C _1-4 -alkoxy group and R⁷ for C _1-4 -alkyl, C _1-4 -alkoxy (low) -alkyl, (2-methoxyethoxy) methyl or R ^7a , where R ^{7a represents} a tri phenylmethyl group.

The compounds of the general formulas (IIa) and (IIb) can be prepared from optionally substituted benzophenones III by aldol condensation to the tetra-substituted Olefins IV and conversion to tetrazol esters V, subsequent alkylation of the tetrazole unit and reduction of the ester group in compounds VI and VII with subsequent oxidation of the alcohols VIII and IX. This reaction sequence is shown in Reaction Scheme 1 poses.

In reaction scheme 1, R¹ to R⁷ have the above Meanings. The optionally substituted benzophenones The formula (III) can be prepared using the known Friedel-Crafts reaction of a substituted phenyl compound under Lewis acid catalysis, e.g. B. with aluminum chloride in carbon tetrachloride at about 0 ° C. A big Number of substituted benzophenones and their preparation is known, many others are commercially available. For example, many of the starting products are of the formula (III) by G. Olah in Friedel-Crafts and Related Reactions, P. 3, parts 1 and 2, Interscience Publishers, New York, 1964 and the literature citations described therein. The Friedel Crafts reaction can result in a mixture of benzophenones and, if this is the case, you can mix with Separate using common techniques.

The corresponding benzophenone of the formula (III) can be treated with ethyl cyanoacetate in a solvent mixture of glacial acetic acid and an organic solvent, such as benzene or toluene, in the presence of a catalyst, preferably β- alanine. The reaction is allowed to proceed at the reflux temperature of the solvent and the water formed is removed azeotropically with a Dean-Stark water separator or similar device until the formation of the tetrasubstituted olefin IV is substantially complete. The nitrile group in compound IV is then converted into the heterocyclic tetrazole radical of compound V by carrying out the reaction with azidotributylstannane without a solvent or in an inert organic solvent such as benzene, toluene or xylene at the reflux temperature of the solvent.

The 1H-tetrazole compound of formula (V) can then with Using various alkylating agents based on known Alkylate methods. So you can the 1H-tetrazole of the formula (V) with a strong base, such as sodium hydride in one non-reactive solvents such as benzene, toluene, diethyl ether or N, N-dimethylformamide or a mixture thereof, at a temperature of -30 ° C to about 50 ° C and then with an alkylating agent, for example methyl iodide, Ethyl iodide, bromotriphenylmethane and the like or with Isobutylene in the presence of a strong acid, such as sulfuric acid, to treat. The temperature is not critical, it judges generally apply to the one used Alkylating agent. This non-specific alkylation results an isomer mixture of the alkylation products, based on usual methods can be separated, for example by crystallization or chromatography, where one the desired 1-substituted tetrazole compounds VI and 2-substituted tetrazole compounds VII is obtained.

It should be noted that the combination of the reaction conditions with the specific one used Alkylating agents can predominantly provide one isomer. For example gives the alkylation of the compound of formula (V), wherein R¹ and R⁴ are p-fluorine and R², R³, R⁵ and R⁶ is a hydrogen atom, predominantly with isobutylene the 2-isomeric tetrazole as shown in Example 32. Alternatively you can use the conditions of the alkylation reaction vary to the desired tetrazoles VI and VII in proportions to get that vary from about 1: 1 to 5: 1. If the preparation of the compounds of formula (I) is desired is in which R⁷ represents a hydrogen atom, alkylated the compound of formula (V) preferably with a Protecting group such as a triphenylmethyl group. In this case the 2-isomer of compound VIII is predominantly formed, as shown in Example 106. The subsequent removal the protective group then results in a connection of the Formula (I) wherein R⁷ is a hydrogen atom. It is for that Those skilled in the art can thus see that the relative amounts of Alkylation products VI and VII from the reaction conditions and the reagents used are influenced.

The tetrazol esters of the formulas (VI) and (VII) can be combined as a mixture or preferably after separation individually based on a series of known reactions in the Transfer alcohols VIII and IX. According to a pathway the compounds of formula (VI) are hydrolyzed first using known methods, for example basic ones Hydrolysis such as with lithium hydroxide, potassium hydroxide and Sodium hydroxide. The acid obtained (see Example 5) is then converted into an acid chloride (Example 6A) by reaction with a reagent such as oxally chloride in methylene chloride Reflux temperature transferred. The acid chloride obtained is reduced with a reducing agent, preferably Lithium aluminum hydride in tetrahydrofuran at -78 ° C, too the alcohols of the formula (VIII). The alcohols of the formula (IX) can be obtained from the esters of the formula (VII) by a produce a similar sequence of reactions for the conversion the ester VI is used in the alcohols VIII. Alternatively and particularly preferably alcohols VIII and IX in one stage from the corresponding esters VI and VII by reduction with reducing agents such as diisobutyl aluminum hydride in a non-reducible internal solvent, like methylene chloride, at low temperatures, preferably at about -78 ° C.

The mixture of the allyl alcohols of the formulas (VIII) and (IX) can be easily by means of conventional oxidizing agents, such as Pyridinium chlorochromate, in a non-reactive solvent, preferably methylene chloride at ambient temperature oxidize. It is particularly preferred to separate the allyl alcohols of formulas (VIII) and (IX) individually in the same Way to the corresponding allyl aldehydes of the formulas (IIa) and (IIb) to oxidize.

The compounds of the formula (I) can be prepared from the compounds of the formulas (IIa) or (IIb) using various alternative reaction sequences via different classes of new intermediates. It should be noted that the preparation of the compounds of formula (I) in which n is 0, 1 or 2 necessarily involves three new aldehyde intermediates. Accordingly, if the preparation of the compounds of the formula (I) in which n = 0 is desired, the compounds of the formulas (IIa) or (IIb) are subjected to a corresponding anion alkylation, as described here. If, on the other hand, the preparation of the compounds of the formula (I) is desired in which n = 1 or 2, appropriate Wittig reactions are carried out in order to obtain the required new homologous aldehydes X and XI for the 1 isomer and the aldehydes XII and XIII for to obtain the 2-isomer as shown in Reaction Schemes 2 and 3.

In Reaction Schemes 2 and 3, R¹, R², R³, R⁴, R⁵, R⁶, R⁷ are as previously defined. R⁷ can also represent R ^7a , where R ^{7a represents} a triphenylmethyl group. According to Reaction Scheme 2, for example, an aldehyde of formula (IIa) can be treated with triphenylphosphoranylidene acetaldehyde in a non-reactive solvent such as benzene, toluene, tetrahydrofuran, 1,2-dimethoxyethane and the like. The reaction temperature is not critical, it can range from ambient to the reflux temperature of the solvent. The reaction is expediently carried out at the reflux temperature. It should be emphasized that the reaction conditions and the number of equivalents of triphenylphosphoranylidene acetaldehyde which are used per equivalent of a compound of the formula (IIa) are of importance. If only one equivalent or slightly more than one equivalent of the Wittig reagent is used without carefully controlling the reaction conditions, for example the time, temperature, mode of addition and the like, a mixture of the dienaldehydes X and the trienaldehydes XI can form. The ratio of the aldehydes X and XI naturally depends on the reaction conditions used. According to Example 8, the aldehydes of the general formulas (X) and (XI) are obtained in a ratio of about 9: 1 from the corresponding aldehyde of the general formula (IIa). The Wittig reaction can also be used for the selective reaction and Support separation of compounds by using less than 1 equivalent of the Wittig reagent to predominantly produce the diene aldehyde X. For example, the use of a 1/2 equivalent of the Wittig reagent, as described in Example 69, gave the desired diene aldehyde X and unreacted aldehyde IIa, which could now be more easily removed. The reaction is preferably carried out with about 1 equivalent of Wittig reagent under controlled reaction conditions, for example as described in Example 77, in order to produce the desired diene aldehyde X without an amount (detectable by NMR) of the homologous trienaldehyde. However, if it is desired to prepare the trienaldehydes of formula (XI), the reaction of the aldehyde of formula (IIa) is carried out with at least 2 equivalents of the Wittig reagent. Alternatively, the dienaldehyde X is reacted with another equivalent of the Wittig reagent to obtain the trienaldehyde of the formula (XI). It can thus be seen that the desired homologous aldehydes X and XI, where n stands for 1 or 2, can be prepared, if desired, by using suitable amounts of Wittig reagent and selecting appropriate reaction conditions.

The conversion of an aldehyde of formula (IIb) into the corresponding one homologous dienaldehyde of the formula (XII) and the Trienaldehyde of formula (XIII) as shown in Reaction Scheme 3 can be done using similar procedures as they are for the preparation of the aldehydes of the formulas (X) and (XI) were. It should be noted that some of the vinylogenic aldehydes in reaction schemes 2 and 3 easily can be isolated, whereas isolating others is difficult. In certain cases, namely when the Aldehydes based on the chromato used here graphics processes are difficult to separate, you set the Mixture of the aldehydes, for example the aldehydes X and XI, in the next stage, where the separation and Isolation of the diene and triene compounds easier using Chromatography or other common methods can be done.

The compounds of the formula (I), in which X is -OH, can be obtained from a compound of the formula (IIa), (IIb), (X), (XI), (XII) or (XIII) using the procedure in reaction scheme 4 produce the reaction sequence shown. For reasons of clarity, the aldehydes shown in Reaction Schemes 2 and 3 have been summarized in a formula for the sake of simplicity; they are referred to as compounds of formula (XIV) wherein n is 0, 1 or 2 and R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined.

The intermediate of formula (XV) shown in Scheme 4, wherein R⁹ is a hydrolyzable ester group, such as methyl, ethyl or t-butyl ester, can be prepared from the corresponding aldehyde of formula (XIV) by reacting the dianion of the acetoacetate ester which is prepared in situ as described in Examples 10 and 90. The reaction can be carried out in an inert organic solvent such as tetrahydrofuran at low temperatures from -78 ° C to about 0 ° C and preferably from about -78 ° C to -40 ° C until the reaction is essentially complete. If a compound of the formula (XV) is prepared from a mixture of the aldehydes of the formula (XIV), the separation and isolation of the compounds of the formula (XV), in particular in which n is 1 or 2, can advantageously be carried out at this stage using conventional methods Techniques are done.

The ketone ester of formula (XV) can be used in the dihydroxy ester of formula (Ia) by reducing the ketone residue with known reducing agents, such as sodium borohydride, Sodium cyanoborohydride, tin borohydride, disiamylborane, Diborane, ammonia borane, t-butylamine borane, pyridine borane, Lithium tri-s-butylborohydride or similar reducing agents, which neither reduce nor reduce the carboxylic ester residue hydrolyze. The reduction is preferably carried out in stereospecific way using a stereospecific Two-stage reduction through to the manufacture of the preferred Maximize erythro isomer of the compounds of formula (I). The stereospecific reduction of a compound of the formula (XV) is carried out with tri-substituted alkyl boranes, preferably triethylborane or alkoxydialkylborane, preferably Methoxydiethylborane or ethoxydiethylborane (tetrahedron Letters, 28, 155 (1987)) at a temperature of about -70 ° C to about ambient temperature. The educated Then complex with sodium borohydride at one temperature from about -50 ° C to about -78 ° C in an inert organic Solvents such as tetrahydrofuran, diethyl ether and 1,2-di methoxyethane, preferably tetrahydrofuran, reduced. The Reduction is then ended by adding methanol. The Compound obtained from the stereospecific reduction of the formula (Ia) contains two asymmetric carbon atoms, which have the hydroxy group in erythro configuration. The reduction of the ketone residue among those used here coming conditions provides the main thing erythro isomers of the compounds of formula (Ia) and only the less preferred threo isomers in small amounts. The ratio of the erythro-threo isomers formed varies according to the compounds used and the Reaction conditions. This ratio is usually about 9: 1 to 9.8: 0.2. A non-specific reduction but usually provides a mixture of the isomers in the Ratio of 1: 1. This mixture of isomers can be separated and cleaned by usual methods and then in the usual way into the compounds of the general formula (I) be transferred.

The compounds of formula (I) in which X in radical A is -OH and R⁸ is a hydrogen atom (Ic), a hydrolyzable ester group (Ia) or a cation to form a non toxic pharmaceutically acceptable salt (1b) means and where A is in the form of a lactone (Id), one can Prepare according to the reaction sequence shown in Reaction Scheme 5 and convert into each other if desired.

In Reaction Scheme 5, R¹, R², R³, R⁴, R⁵, R⁶, tet and n are as previously defined, R⁹ represents a hydrolyzable ester group and M⁺ represents a cation. A compound of formula (Ib) is preferably prepared from a compound of formula (Ia) by basic hydrolysis with bases such as sodium hydroxide, potassium hydroxide and lithium hydroxide in an organic solvent such as tetrahydrofuran, ethanol and methanol at a temperature of 0 ° C up to about 50 ° C. The cation generally corresponds to the cation of the hydroxide used. If desired, however, the cation can be exchanged for another cation by treatment with ion exchange resins.

The compounds of formula (Ic) can be added to the corresponding ones Lactone compounds of the formula (Ib) using conventional Lactonization methods cyclize, for example by the acid in an inert organic solvent, such as Benzene, toluene and xylene heated and the water formed removed azeotropically or by using a compound of formula (Ic) in an inert organic solvent, for example Toluene, benzene, diethyleter or methylene chloride, with an acid, such as p-toluenesulfonic acid, in the presence of a Drying agents, for example NaSO₄, MgSO₄ or molecular sieves, treated. Lactonization is preferably carried out by activation of the carboxyl radical with a carbodiimide, in an inert organic solvent such as tetrahydrofuran and preferably in methylene chloride or ethyl acetate, at about ambient temperature, taking the lactone Formula (Id) is obtained. If the two carbon atoms, which one which have hydroxyl groups, stereo-chemical erythro configuration possess, then the lactonization leads to the preferred trans lactones of formula (Id), whereas these Lactonization otherwise a mixture of trans and cis Lactones supplies.

If desired, the lactones of the formula obtained (Id) with a base or acid to the compounds of Formula (Ib) or (Ic) can be hydrolyzed. The lactone can even in the presence of an alcohol to the compounds of Formula (Ia) are hydrolyzed.

The compounds of formula (I) in which in the definition of the substituent A the radical X is = O, can be by Implementation of a corresponding aldehyde of the formula (XIV) with a phosphonate compound of the formula (XVI), as shown in Reaction Scheme 6.

In Reaction Scheme 6, R¹, R², R³, R⁴, R⁵, R⁶, tet and n are as previously defined and R⁹ is a hydrolyzable ester group. The preparation of a compound of formula (Ie) can be carried out according to Reaction Scheme 6 in an inert organic solvent such as acetonitrile, methylene chloride, chloroform, tetrahydrofuran and the like at a temperature from 0 ° C to the reflux temperature of the solvent and preferably at ambient temperature in the presence of a suitable one organic base. Suitable organic bases are e.g. B. tertiary amines such as triethylamine, N-methyl morpholine, N-methylpiperidine, 1,4-diazobicyclo [2.2.2] octane ("DABCO"), 1,8-diazabicyclo [5.4.0] undec-7-ene ( "DBU"), 1,5-diazabicyclo [4.3.0] non-5-ene ("DBN") and the like. The resulting compounds of formula (Ie), in which R⁹ is a hydrolyzable ester group, can, if desired, be hydrolyzed by conventional methods to give compounds of formula (I) in which R⁹, as described and explained in Reaction Scheme 5, is converted into the substituents R⁸.

According to an alternative reaction sequence, a preferred embodiment of the compounds of the formula (I), in which n is 1, X is -OH and tet is 1-methyl-1H-tetrazol-5-yl, can be carried out in accordance with the process described in reaction scheme 7 produce.

In Reaction Scheme 7, R¹, R², R³, R⁴, R⁵ and R⁶ are as before defined, R⁹ means a hydrolyzable ester group, R¹⁰ stands for t-butyldiphenylsilyl and Z stands for

wherein R¹² represents a C _1-4 alkyl group, R¹³ represents a phenyl group which may be unsubstituted or substituted by one or two C _1-4 alkyl or chlorine radical (s) and X represents bromine, chlorine or iodine. The phosphonium salt of the formula (XVII) or the phosphonate of the formula (XVIIa), which is described here, can be reacted with the silyl group-protected aldehyde of the formula (XVIII), which is described in Tetrahedron Letters, 25, 2435 (1984) and in the process described in US Pat. No. 4,571,428 is produced, are converted to the silyl-protected compound of the formula (XIX). The reaction can be carried out in an inert organic solvent, such as tetrahydrofuran and N, N-dimethylformamide, in the presence of a strong base, for example lithium diisopropylamide, n-butyllithium or potassium t-butoxide, at a temperature of about -78 ° C to about 0 ° C. The compounds of formula (XIX) can then be easily desilylated using known methods, e.g. B. with 48% hydrofluoric acid and preferably with tetrabutylammonium fluoride, in an inert organic solvent, such as tetrahydrofuran and acetonitrile, giving the erythro compounds of the formula (If), which are a more preferred embodiment of the compounds of the formula (Ia) . The substituent R⁹ can then be converted into the substituent R⁸, as described and in Reaction Scheme 5, he explains.

If desired, predominantly a stereoisomer of one To produce the compound of formula (I), it is preferred to use optically pure starting materials. The different Process for the preparation of an isomer of a Compound of formula (I) wherein X is -OH is used are in Reaction Schemes 8, 9 and 10 explained. The most preferred isomer of the compounds of formula (I), wherein A is

is the (3R, 5S) isomer and the most preferred Isomer of the compounds of formula (I), wherein A is

is the (4R, 6S) isomer. It should be noted that one of the two definitions for A in the compounds of formula (I) suffice because these are converted into one another as shown in Reaction Scheme 5 can be. To apply optically pure output Showing materials is making a favorite Embodiment of the compounds of formula (I), such as the (3R, 5S) isomers of the compounds of formula (If), on three Synthetic routes shown in Reaction Schemes 8, 9 and 10.

In Reaction Scheme 8, R¹, R², R³, R⁴, R⁵, R⁶ are as before defined and R¹⁰ means a t-butyldiphenylsilylrest. The starting materials XX and XXII are known and theirs Manufacture is in Tetrahedron Letters, 23, 4305 (1982) and US-PS 46 13 610 described. The compounds of the formula (XVII) or (XVIIa) can with the compounds of Formula (XX) in an inert organic solvent implement the compounds of formula (XXI), which subsequently with an acid in a solvent mixture hydrolyzed from acetic acid, tetrahydrofuran and water and mild oxidation with pyridinium chlorobromate in methylene chloride can be subjected to the desired trans- To provide lactone of formula (XXIII). Alternatively, you can Prepare trans-lactones of the formula (XXIII) directly by Condensation of a compound of formula (XXVII) and one Compound of formula (XXII). Desilylation with 48% Hydrogen fluoride in acetonitrile and preferably with tetra Butylammonium fluoride then provides the (4R, 6S) enantiomer the compounds of formula (Ig), which if desired into the (3R, 5S) enantiomer of a compound of Formula (If) can be transferred.

The second stereo-specific pathway is in the reaction scheme 9 shown in which R¹, R², R³, R⁴, R⁵ and R⁶ as before are defined, R⁹ is a hydrolyzable ester group and R¹⁰ represents t-butyldimethylsilyl. The dienaldehyde of the formula (Xa) is treated with sodium cyanide and the cyanohydrin thus obtained is converted into the tetra hydropyranyl (THP) derivative of the formula (XXIV). The connection of formula (XXVI) can be prepared by using a compound of formula (XXIV) initially with a strong base, like n-butyllithium, and then with the iodo ester of the formula (XXV) treated. The manufacture of the optically pure protected Iodohydrins (XXV), wherein R¹⁰ is t-butyldimethylsilyl stands and R⁹ represents a methyl group, is in Tetrahedron Letters, 25, 2951 (1985). The distance the protective groups can be removed by acid hydrolysis Formation of the keto alcohol of the formula (XXVII) take place. The stereo-specific reduction of a compound of the formula (XXVII) using sodium borohydride-triethylborane or sodium borohydride alkoxyl dialkylborane, as described here, can be used to add the 5-keto group to the desired (5S) stereo-chemical arrangement with formation of the (3R, 5S) enantiomer of the compound of formula (If) to reduce. Reaction scheme 9 accordingly shows a method for the preparation of the (3R, 5S) isomer of a compound of Formula (I) using the optically pure output materials (XXV), which the correspondingly substituted Carbon atom in the 3-position provides the to conduct stereo-specific reduction of the 5-keto function.

The third stereo-specific pathway is in the reaction scheme 10, wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ as are previously defined. The starting material of formula (XXVIII) and its manufacture is in Tetrahedron Letters, 25, 5031 (1984). The compound of formula (XXVIII) first with a non-nucleophilic base, preferably Lithium diisopropylamide, in an inert solvent, treated like tetrahydrofuran. The enolate thus obtained is then with an allyl aldehyde of formula (Xa) Triphenyl ester of the formula (XXIX) implemented. If you connect of the formula (XXIX) with sodium methoxide in methanol treated, you can isolate the methyl ester of formula (XXX). If the methyl ester of formula (XXX) with the anion of t-butyl acetate, which is reacted in situ with a non- nucleophilic base, such as lithium diisopropylamide, the ketoester of the formula (XXXI) is formed. Alternatively a compound of the formula (XXXI) can be prepared, by using the triphenyl ester of formula (XXIX) directly treated with the anion of the t-butyl ester. The selective stereospecific reduction of the keto function obtained Formula (XXXI) with sodium borohydride-triethylborane or Sodium borohydride alkoxydialkylborane as described here one can use the (3R, 5S) -enantiomer of a compound of the formula (If). The reaction scheme 10 accordingly describes a method for producing the (3R, 5S) isomer of a compound of formula (I) by application an optically pure starting material XXVII, which the appropriately substituted carbon atom in the 5-position Provides the stereo-specific reduction of the Conduct 3-keto function. In one of the described here Examples where R¹ and R⁴ represent a fluorine atom and R², R³, R⁵ and R⁶ represent a hydrogen atom, becomes a process for the preparation of a compound of the formula (If), which is mainly the (3R, 5S) enantiomer.

According to a preferred embodiment, they have Compounds of formula (I) according to the invention have the structure:

wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; n represents an integer from 0 to 2 inclusive, Afür R, is hydrogen, C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl; X is -OH or = O; and R⁸ represents a hydrogen atom, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt.

According to a more preferred embodiment, they have Compounds of formula (I) according to the invention have the following structure:

wherein R¹ to R⁶ each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; R⁷ represents a C _1-4 alkyl group; and R⁸ represents a hydrogen atom, a C _1-6 alkyl group or a cation to form a non-toxic pharmaceutically acceptable salt. R⁷ is particularly preferably a methyl group.

Another preferred embodiment is the connections of formula (I):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; and R⁷ represents a C _1-4 alkyl group. According to a particularly preferred embodiment, R⁷ represents a methyl group.

The particularly preferred compounds according to the invention are:

• (a) ethyl-9-9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1- methyl 1H-tetrazol-5-yl) -6,8-nonadienoate,
• (b) 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable Salt,
• (c) sodium 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate,
• (d) (3R, 5S) enantiomer of 9,9-bis (4-fluorophenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nona diencarboxylic acid or a non-toxic pharmaceutical tolerable salt,
• (e) (3R, 5S) enantiomer of sodium 9,9-bis (4-fluorophenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6.8- nonadienoat,
• (f) trans-6- [4,4-bis- (4-fluorophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one.
• (g) (4R, 6S) enantiomer of trans-6- [4,4-bis (4-fluoro- phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one.
• (h) 11,11-bis (4-fluorophenyl) -3,5-dihydroxy-10- (1-methyl- 1H-tetrazol-5-yl) -6,8,10-undecatrienecarboxylic acid or a non-toxic pharmaceutically acceptable Salt,
• (i) sodium 11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- (1-methyl-1H-tetrazol-5-yl) -6,8,10-undecatrionoate,
• (j) trans-6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-2H- tetrazol-5-yl) -1,3-butadienyl] tetrahydro 4-hydroxy-2H-pyran-2-one,
• (k) 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl- 2H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (l) sodium 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazol-5-yl) -6,8-nonadienoate,
• (m) 9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl-1H- tetrazol-5-yl) -5-oxo-6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (n) Sodium-9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate,
• (o) 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (1-methyl- ethyl) -1H-tetrazol-5-yl] -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (p) Sodium-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -6,8-nona dienoat,
• (q) ethyl 9,9-bis (4-fluorophenyl) -3,5-hydroxy-8- (1-methyl-1H- (1-methylethyl) -1H-tetrazol-5-yl] -6,8-nonadienoate,
• (r) 9,9-bis (4-fluoro-3-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (s) sodium 9,9-bis (4-fluoro-3-methylphenyl) -3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nona dienoat,
• (t) 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-ethyl-1H- tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable salt,
• (u) sodium 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) -6,8-nonadienoate,
• (v) 9,9-bis (2,4-dimethylphenyl) -3,5-dihydroxy-8- (1- methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (w) sodium 9,9-bis (2,4-dimethylphenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate,
• (x) 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (2- methoxyethoxy) methyl-1H-tetrazol-5-yl] -6,8-nona diencarboxylic acid or a non-toxic, pharma tolerable salt,
• (y) sodium 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] - 6,8-nonadienoate,
• (z) 9,9-bis (4-fluoro-2-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic, pharmaceutically acceptable Salt,
• (aa) sodium 9,9-bis (4-fluoro-2-methylphenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6.8- nonadienoat,
• (bb) 9,9-bis (2-fluoro-4-methylphenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadiene carbon acid or a non-toxic, pharmaceutically acceptable Salt,
• (cc) sodium 9,9-bis (2-fluoro-4-methylphenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6.8- nonadienoat.

The invention also relates to new intermediates Formula XIV:

wherein R¹ and R⁴ each independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶ each independently represent hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy.
works for

stands;
n represents an integer from 0 to 2 inclusive; and R⁷ is C _1-4 alkyl, C _1-4 alkoxy lower alkyl, (2-methoxy ethoxy) methyl or R ^7a , where R ^{7a represents} a triphenylmethyl group.

According to a preferred embodiment, the compounds have of the formula (XIV) the structure:

wherein R¹ to R⁴ each independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶ each independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy and n is an integer from 0 to 2 inclusive; and R⁷ is C _1-4 alkyl, C _1-4 alkoxy lower alkyl or 2- (methoxyethoxy) methyl.

A more preferred embodiment are the compounds of Formula (XIV):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; and R⁷ represents a C _1-4 alkyl group. According to a particularly preferred embodiment, R⁷ represents a methyl group.

Another preferred embodiment is the connections of the formula (XIV):

wherein R¹, R², R³, R⁴, R⁵ and R⁶ each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; and R⁷ represents a C _1-4 alkyl group. According to a particularly preferred embodiment, R⁷ represents a methyl group.

Furthermore, the invention relates to new intermediates Formula (XV):

wherein R¹ and R⁴ are each independently hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶ each independently represent hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy; n represents an integer from 0 to 2 inclusive;
works for

stands;
R⁷ is C _1-4 alkyl, C _1-4 alkoxy lower alkyl, (2-methoxyethoxy) methyl or R ^7a , where R ^{7a represents} a triphenylmethyl group; and represents a hydrolyzable ester group.

According to a preferred embodiment, the compounds have of formula (XV) the structure:

wherein R¹ and R⁴ each independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl; R², R³, R⁵ and R⁶ each independently represent hydrogen, halogen, C _1-4 alkyl, C _1-4 alkoxy n is an integer from 0 to 2 inclusive; R⁷ is C _1-4 alkyl, C _1-4 alkoxy lower alkyl or 2- (methoxy ethoxy) methyl; and R⁹ represents a hydrolyzable ester group.

According to a more preferred embodiment, the Ver compounds of formula (XV) the structure:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ each independently represent hydrogen, fluorine, chlorine, methyl or methoxy and R⁷ represents a C _1-4 alkyl group. According to a particularly preferred embodiment, R⁷ represents a methyl group.

The compounds of formula (I) according to the invention are competitive inhibitors of the enzyme 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase, the speedy limiting enzyme in cholesterol biosynthesis. These compounds are therefore selective suppressors of the Animal cholesterol biosynthesis, including the People. They are therefore useful for the treatment of Hypercholesterolemia, hyperlipoproteinemia and arterio sclerose. The biological activity of the compounds of the Formula (I) is based on the three described below biological tests shown.

Test A In vitro inhibition of microsomal HMG-CoA reductase

The intact, fully activated, microsomal form of rat liver HMG-CoA reductase (subunit MW approx. 100,000 Daltons) was produced as described by Parker et al, Biochem. Biophys. Res. Commun. 125, 629-638 (1984) and used as an enzyme source for the assays. The HMG-CoA reductase activity was determined essentially according to the method described by Shapiro et al, Biochem. Biophys. Acta. 370, 369-377 (1974) using the method described by Ingebritsen and Gibson, Meth. Enzymol. 71, 486-497 (1981), with the exception that the internal standard 3 H-mevalonolactone is added after the end of the assay. In this method, the enzyme is determined by measuring the formation of the product ¹⁴C-mevalonate, from the substrate [3-¹⁴C] -HMG-CoA in the presence of NADPH. The ¹⁴C-mevalonate is converted into its lactone and isolated by means of thin layer chromatography (Whatman LK5D, developed with 50:50 benzene: acetone) in the presence of ³H-mevalonolactone as an internal standard. The assays were performed under conditions where the product formation was linear in terms of time and enzyme concentration.

In order to measure the reductase inhibition, the test compounds were dissolved in water or dimethyl sulfoxide and diluted in buffer A (50 mM imidazole HCl, 250 mM NaCl, 1 mM EDTA, 1 mM EGTA, 5 mM DTT, 20 μM leupeptin, pH = 7 , 2), incubated with aliquots of the microsomes (80-160 µg protein in buffer A). Then d, 1- [3-13 C] HMG-CoA (0.33 mM, 2.0 dpm / picomole) and NADPH (3.0 mM) were added. The 50% inhibitory concentration (IC₅₀) for each compound in Table 1 was calculated from the linear regression line of percent decrease (over control) of enzyme activity versus log concentration of inhibitor, determined using at least four dilutions per test compound, which were double were examined:
Connection of example No.IC₅₀ (µmolar)

11 <330 120,037 ± 0.01 131.09 ± 0.29 155.7 440.16 651.6 920.029 990.58 1200.044 1260.19 1321.4

Test B Isolated hepatocyte cholesterol biosynthesis assay

Intact parenchymal hepatocytes were obtained from male Wistar rats (180-280 g), which were supplied with cholestyramine-containing or normal feed, using the collagenase perfusion method as essentially described by Seglen in Methods in Cell Biology (D. Prescott, ed. ), Vol. 13, pp. 29-83, Academic Press, New York (1976). The cell preparations were only used if the viability (trypan blue exclusion) was greater than 90%. Cholesterol biosynthesis was determined as incorporation of 3 H from [3 H] water by hepatocytes in total (cellular plus medium) -3 β- hydroxysterines according to Ingebritsen et al., J. Biol. Chem., 254, 9986-9989 (1979) . The hepatocyte sterols and lipids were isolated by modifying the methods described by Kates in Techniques in Lipidology, (M. Kates, ed.) Pp. 349, 360-386, North Holland Publ. Co., Amsterdam, 1972). To isolate the sterols, the cells were extracted with methanol: chloroform: water (2: 1: 0.8), the chloroform phase was separated and extracted with benzene to remove traces of water, and then dried under nitrogen. The residue is saponified at 75 ° C. with 0.30 N NaOH in methanol: water (9: 1). The alkaline mixture is then extracted three times with petroleum ether to give the unsaponifiable lipids which contain the free as well as the originally esterified cholesterol. The extract is dried under nitrogen in the presence of carrier cholesterol (0.1 mg) and 10% benzene and the residue is dissolved in acetone: ethanol (1: 1). Finally the 3 β- hydroxysterins are precipitated with an excess of digitonin, the precipitate is washed in acetone, dried under nitrogen and dissolved in toluene: methanol (1: 1). The ³H-labeled sterols are quantitatively determined using liquid scintillation and corrected with regard to the counting efficiency. In some experiments, ¹⁴C-cholesterol was added to the original extracts as a recovery index, which gave an average of 80 ± 3%.

To determine the inhibition of cholesterol synthesis, double or triple aliquots of freshly isolated cells (100 mg cell net weight in 2.0 ml) were placed in Eagle's Minimal Essential Medium, which contains bicarbonate and HEPES buffer, pH 7.35, and 2 % Bovine serum albumin suspended in an atmosphere of 95% O₂ +%% CO₂. The cells were preincubated for 10 minutes with or without aliquots of the test compounds, which were added as an aqueous solution of the sodium salts or as a dimethyl sulfoxide solution of the lactones. In the control approaches, the carrier was present alone. Subsequently, [3 H] water (1.0 mCi per ml incubation volume) or 2 -11 C acetate (0.5 µCi per ml incubation volume) were added, and the cells were incubated for 60 min at 37 ° C. with constant shaking. These conditions led to the linear incorporation of lithium or ¹⁴C into the sterols. The IC₅₀ values for the inhibition of sterol synthesis by the test compounds, which are summarized in Table 2, were calculated from the linear regression curve of the percentage inhibition (compared to the control) against the log concentration using at least four inhibitor concentrations. Test B therefore measures the ability of the test compounds to inhibit the intracellular synthesis of cholesterol.
Compound of Example No.IC₅₀ (nmolar)

1223.0 ± 11 1324.0 1387.4 Mevinolin (Lovastatin) 46.0 ± 26

Test C In vivo acute inhibition of cholesterol biosynthesis in Rats

Male Wistar rats (160-200 g, 2 animals per cage) were with normal food (Purina rat food and water ad libitum) under reverse lighting conditions (7 a.m. to 5 p.m. Clock in the dark). The feed was 15 h before administration the test connections removed. The connections were used at 8:00 am by intragastric intubation from 0.5 to 1.0 ml of a solution of the sodium salts, Lactones or esters of the test compounds in water or Propylene glycol administered. The control animals received equal volumes of carriers.

30 minutes after administration of the test compounds Rats intraperitoneally 0.9 ml of a 0.9% NaCl solution administered, which about 120 µCi per kg body weight Contained sodium [1-¹⁴C] acetate (1-3 mCi / mmol). After 60 min. the rats were sacrificed and the liver and blood samples were taken taken. Aliquots of plasma (1.0 ml) obtained from Centrifuging heparin + EDTA-treated blood, and aliquots of liver homogenates (corresponding to 0.50 g Liver Moisture) were radiolabeled for the determination 3-hydroxysterine used. The sterol isolation from the liver samples was done according to the Kates method, as described above in connection with the hepatocytes (test B). In contrast, the plasma samples were saponified directly, the digitonin was then isolated precipitable sterols. The ¹⁴C-labeled sterols were quantitatively using liquid scintillation counting (Efficiency corrected) determined. The mean percentage Inhibition of in the liver and in plasma cholesterol built-in ¹⁴C were calculated for the treated groups of animals and ver with the mean values for the control animals like.

Test C provides information about the ability of the test compounds the de novo biosynthesis of cholesterol in vivo suppress in rats and when administered orally. In Test C, for example, the compound of Example 12 gave a 50% inhibitory dose (ED₅₀) of 0.08 mg / kg for both plasma and liver cholesterol. For the Ver However, the same compound mevinolin had an ED₅₀ value of Obtained 0.04 mg / kg, which was comparable to the values which obtained with mevinolin using a similar procedure (Alberts et al., Proc. Natl. Acad. Sci., 77, 3957-3961 (1980)).

The results of in vitro and in vivo tests A, B and C show that the compounds of formula (I) the cholesterol Inhibit biosynthesis and therefore for the treatment of hyper cholesterolemia are useful.

The invention also relates to pharmaceutical compositions, the at least one compound of formula (I) in combination with a pharmaceutical carrier or diluent contain.

The invention further relates to a method for inhibition animal cholesterol biosynthesis, including the People who need such treatment. The procedure is that you have an effective, cholesterol inhibitory dose of at least one compound of the formula (I) administered.

The pharmacologically effective ones are used for therapeutic purposes Compounds of formula (I) in general as pharmaceutical agent administered as essential Part of at least one of these compounds together with a solid or liquid pharmaceutically acceptable Carrier and if desired together with pharmaceutically acceptable Contains adjuvants and excipients, whereby one uses common techniques.

The pharmaceutical agents can be taken orally, parenterally or administer rectally as suppositories. You can have a variety Use pharmaceutical forms. If a firm Carrier is used, the preparation can be tabletted, or in a hard gelatin capsule in powder or pellet form or can be in the form of a lozenge or Lozenge available. The solid support can be conventional Excipients contain, such as binders, fillers, tableting Lubricants, disintegrants, wetting agents and the like. If desired, the tablet can be removed using usual methods covered with a film. When a liquid carrier is used, the preparation can as syrup, emulsion, soft gelatin capsule, sterile carrier for injection, aqueous or non-aqueous liquid Suspension or it can be made from dry products Reconstruction with water or another suitable one Carrier should be used before use. Liquid preparations can contain conventional additives, such as suspending agents, Emulsifiers, non-aqueous vehicles (including edible Oils), preservatives and flavorings and / or Dyes. For parenteral administration, the Carrier usually sterile water, at least to a large extent Part, but you can also use saline solutions, glucose solutions and the like apply. Also injectable suspensions can be used using conventional suspending agents starts. Usual preservatives, buffers and the like can also be used in parenteral dosage forms are given. The pharmaceutical means on the basis of customary, suitable for the desired preparation Methods produced and contain appropriate amounts of Compound of the formula (I) according to the invention as active ingredient.

The dosage of the compounds of formula (I) does not depend only factors such as the patient's weight or the Type of administration, but also on the desired degree inhibition of cholesterol biosynthesis and effectiveness the connection used. The decision about the actual dosage (and the number of Administration of medication per day) is the judgment of the doctor left. The dosage can vary according to the special circumstances be varied to achieve a satisfactory inhibition or Achieve reduction in cholesterol biosynthesis. Each oral dose unit contains the active ingredient in an amount of about 0.01 mg / kg to about 10 mg / kg body weight, preferably about 0.05 mg / kg to about 2 mg / kg body weight. The Active ingredient is preferably in equal doses 1 to 4 × each Administered day. In general, however, a small one Dose administered, gradually increasing the dose until the optimal dose for the person to be treated Patient is determined.

A particularly preferred method of making a more preferred embodiment of the compounds according to the invention of the formula (IIc)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, is in the application filed on the same day Applicant (M / 29 055).

The compounds of formula (IIc) can be found in produce different processes, preferably from one Compound of the general formula (XXXII)

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined and R¹¹ is hydrogen, C _1-6 alkoxycarbonyl or methyl.

The use of the compounds of formula (XXXII) leads to an advantageous and selective process, which the alkylation mixtures described in Reaction Scheme 1 avoids.

The compounds of formula (XXXII) can optionally be obtained from the substituted benzophenones of formula (III) by alkylation with the appropriate 5-substituted 1-methyltetrazole of formula (XXXIII) and subsequent Dehydration of the tertiary alcohol of the formula obtained Prepare (XXXIV) as shown in Reaction Scheme 11 is.

In Reaction Scheme 11, R¹, R², R³, R⁴, R⁵, R⁶, and R¹¹ are as previously defined. The optionally substituted benzophenones of the formula (III) can be prepared by the known Friedel-Crafts reaction. The starting material of formula (XXXIII), wherein R¹¹ represents a hydrogen atom, is commercially available, whereas the starting materials, wherein R¹¹ represents C _1-6 alkoxycarbonyl or methyl, can be prepared by using 1,5-dimethyltetrazole with a strong Base, such as butyllithium, at a temperature of about -70 ° to about 0 ° C and preferably the resulting anion is added to or treated with ethyl chloroformate or methyl iodide as described here.

The corresponding 5-substituted 1-methyltetrazole of the formula (XXXIII) can with a strong base, such as n-butyllithium, at low temperatures from about -20 ° C to about -78 ° C, and preferably from about -40 ° C to -78 ° C, in one inert organic solvents, e.g. B. tetrahydrofuran, Treat diethyl ether, 1,2-dimethoxyethane and the like. The anion of formula (XXXIII) obtained can then with treat the desired benzophenone of formula (III), wherein the corresponding tertiary alcohols of the formula (XXXIV) receives.

The compounds of formula (XXXII) can be obtained from the compounds of the formula (XXXIV) by customary dehydration processes receive. Dehydration can be done by heating the alcohol of formula (XXXIV) in a suitable inert organic solvents, such as toluene, benzene or Xylene, with a small amount of an organic acid or a mineral acid, such as p-toluenesulfonic acid or sulfuric acid, in the presence of a drying agent, such as Na₂SO₄, MgSO₄, molecular sieves, etc., make. Preferably removed but the water formed is azeotropically with a Dean Stark water separator or a similar device.

Alternatively, the alcohol of formula (XXXIV) can simply be added Potassium bisulfate heated at a temperature of about 190 ° C will.

When R¹¹ is ethoxycarbonyl, the reaction of Ethyl 1-methyl-5-tetrazolylacetate with a benzophenone Formula (III) in the presence of titanium tetrachloride and tetra Chlorinated carbon can be carried out, directly in a Step the corresponding olefin of formula (XXXII) obtained becomes.

The preferred aldehydes of the formula (IIc) can be obtained by various processes from the compounds of the formula (XXXII) depending on the kind of the substituent R¹¹ produce. It should be noted that the connections of the Formula (XXXII), wherein R¹¹ is ethoxycarbonyl (XXXIIa), Is hydrogen (XXXIIc) or methyl (XXXIId), in the Aldehydes of formula (IIx) as shown in Reaction Scheme 12 can be transferred.

In Reaction Scheme 12, R¹, R², R³, R⁴, R⁵und R⁶ are like previously defined. The alcohols of the formula (XXXIIb) can be used preferably produce in one step by reduction the tetrazole ester of the formula (XXXIIa) with reducing agents, like diisobutyl aluminum hydride in a non-reducible inert solvents such as methylene chloride and tetrahydrofuran, at low temperatures and preferably at about -78 ° C. The allyl alcohols of the formula (XXXIIb) obtained can then easily with conventional oxidizing agents, such as Pyridinium chlorochromate, in a non-reactive solvent, preferably methylene chloride, at ambient temperature oxidize, giving the desired aldehyde of the formula (IIc) receives. The compounds of formula (XXXIIc) can convert directly into the aldehydes of the formula (IIc) by the anion of the formula (XXXIIc), which one in situ in a inert organic solvents, e.g. T. tetrahydrofuran or 1,2-dimethoxyethane with a strong base, such as n-butyllithium received, treated with ethyl formate.

The compounds of formula (IIc) can also be obtained from Ver Make bonds of formula (XXXIId) by first the compounds of formula (XXXII) with N-bromosuccinimide in the presence of a catalyst such as azobis-isobutyronitrile or benzoyl peroxide, treated in carbon tetrachloride and then the allyl bromide of the formula (XXXIIe) obtained with 2-nitropropane according to the here and in Org. Syn. Coll. Vol. IV, 932 implement general procedures. Alternatively the allyl bromide of the formula (XXXIIe) can be obtained from the Alcohol of formula (XXXIIb) by treatment with coal produce tetrabromide and triphenylphosphine.

According to an alternative and preferred method of manufacture of the compounds of formula (If) are the intermediates of formulas (XVII) and (XVIIa), as in the reaction scheme 13 shown, provided.

In Reaction Scheme 13, R¹, R², R³, R⁴, R⁵, R⁶, R¹², R 13 and X are as previously defined. The allyl bromide of the formula (XXXIIe) can in the usual way with phosphines, such as Triphenylphosphine, in an inert organic solvent, such as cyclohexane, to the phosphonium salt of the formula (XVII]. Alternatively, the allyl bromide of Formula (XXXIIe) in the usual way with phosphites, such as Trimethyl phosphite and triethyl phosphite, either in bulk or in an inert organic solvent, preferably however in substance to the phosphonates of the formula Implement (XXVIIa).

The intermediates of formulas (XVII) or (XVIIa) can in the compounds of the formula (If) by the in Transfer reaction scheme 7 shown reaction sequence.

Another particularly preferred method of making it compounds of the formula (If) and (Ig) according to the invention using the intermediates of the formulas:

<; V 99999 00070 552 001000280000000200012000285919988800040 0002003805801 00004 99880ER NB = 1 <essentially in cis form, where R¹⁶ and R¹⁷ each represent C _1-4 alkyl or R¹⁶ and R¹⁷ together with the carbon atom to which they are attached for Cyclopentyl, cyclohexyl or cycloheptyl and R¹⁹ represents hydrogen, C _1-4 alkyl or a metal cation.

The substituted 1,3-dioxane compounds of the formula (XXXVa), (XXXVb) and other similar compounds described here are also two asymmetrical 4- and 6-position carbon atoms:

The four stereoisomers obtained are called (4R, 6S), (₄R, 6R) and (4S, 6S) stereoisomers. The expression "trans" - 1,3-dioxane comprises a mixture of the (4R, 6R) and (4S, 6S) enantiomers, whereas the term "cis" -1,3-dioxane is a Mixture of the (4R, 6S) and (4S, 6R) enantiomers. Since that most preferred enantiomer of the lactone compounds of the formula (Ig) happens to have the same (4R, 6S) stereochemical name as the most preferred enantiomer of the 1,3-dioxane intermediates has "trans" or "cis" specified to avoid confusion.

The compounds of the formulas (XXXVa) and (XXXVb) can be used produce by using an aldehyde of formula (XXXVI) an ester of acetoacetic acid and then a Ketone or ketal with a compound of formula (XXXVIII) brings to reaction, then the 1,3-dioxane obtained Formula (XXXIX) hydrolyzes and, if desired, the acid of the formula (XXXX), as in reaction scheme 14 ge shows.

In Reaction Scheme 14, R¹⁴ and R¹⁵ each independently represent hydrogen, C _1-4 alkyl or phenyl, which is optionally substituted by one or two C _1-4 alkyl, halogen, C _1-4 alkoxy or trifluoromethyl; R¹⁸ represents a hydrolyzable ester group, m represents 0 or 1 and R¹⁶ and R¹⁷ are as previously defined. The ketoester of formula (XXXVII) can be prepared by using an ester of acetoacetic acid with an aldehyde of formula (XXXVI) according to known methods in an inert organic solvent such as tetrahydrofuran at temperatures from about 0 ° C to about -78 ° C in the presence of a base such as sodium hydride, lithium diisopropylamide and n-butyllithium.

The starting materials of the formula (XXXVI), in which m = 0 and m = 1, are known or can be easily prepared using known methods. The starting materials of formula (XXXVI), in which m = 1, can also be prepared by reacting the compounds of formula (XXXVI), in which m = 0, with Wittig reagents, such as triphenylphosphoranylidene acetaldehyde, and other known processes. It should be noted that the relative configuration of the double bond (m = 0) or double bonds (m = 1) in the starting materials of formula (XXXVI) can be trans, cis or mixtures thereof. The relative amounts of each geometric isomer (I) or (Z) is determined by the commercial products or the reaction conditions used in the manufacture. According to an example described here, a mixture was used which predominantly contains the trans (E) isomer. Even though a small percentage of the other isomer is present in the reaction sequence shown in Reaction Scheme 14, those skilled in the art are aware that the relative amount of isomers is not critical because the double bond is oxidized and removed in the ozonolysis reaction.

The keto ester of the formula (XXXVII) can be used in the dihydroxy ester of the formula (XXXVIII) by reducing the keto group with transfer known reducing agents. Preferably the Response stereo-specific in a two-stage stereo-specific Reduction done to maximum formation of the preferred erythro isomer of the dihydroxy ester of the formula (XXXVIII). The stereo-specific reduction leads one with trisubstituted alkyl boranes, preferably Triethylborane or tri-n-butylborane, or with alkoxydialkylboranes, preferably methoxydiethylborane or ethoxydiethylborane (Tetrahedron Letters, 28, 155 (1987)) in one Temperature from about -70 ° C to about ambient temperature. The The complex formed is then mixed with sodium borohydride at a Temperature from about -50 ° C to about -78 ° C in an inert organic solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, preferably tetrahydrofuran, reduced. The reduction is achieved by adding methanol or without adding aqueous hydrogen peroxide and buffer completed. Some of the compounds of formula (XXXVIII) are known and in US-PS's 42 48 889 and 46 50 890 described.

The compounds of the formula (XXXIX) can be obtained from the compounds of the formula (XXXVIII) produce by reaction with a ketone such as 2-propanone, 3-pentanone, cyclopentanone and Cyclohexanone, in a suitable inert organic solvent, such as toluene, benzene or xylene, at temperatures of about 20 ° C to the reflux temperature of the solvent in Presence of a small amount of an organic acid, Mineral acid or an acid resin, e.g. B. p-toluenesulfone and sulfuric acid. The water formed is removed if necessary with a drying agent, e.g. B. Na₂SO₄, MgSO₄ and Molecular sieves, or azeotropic with a Dean-Stark water separator or a similar device. The implementation a compound of formula (XXXVIII) with a ketone can perform without solvent. Alternatively, the above reaction of the compounds of formula (XXXIX) with a Ketal such as 2,2-dimethoxypropane, 1,1-dimethoxycyclohexane and the like.

The compounds of formula (XXXVa), in which R¹⁹ represents a hydrolyzable ester group and preferably represents C _1-4 alkyl, can be prepared from the corresponding compounds of formula (XXXIX) by oxidation of the olefin in an aldehyde group using conventional methods. Alternatively, a compound of formula (XXXIX) is first hydrolyzed basic to a compound of formula (XXXX), which is then oxidized to a compound of formula (XXXVa) in which R¹⁹ represents a hydrogen atom. A particularly useful oxidation method is the reaction of a compound of the formula (XXXIX) or (XXXX) in an inert organic solvent, such as methanol, ethyl acetate and methylene chloride, with ozone at temperatures from about -50 ° C to about -78 ° C. When the reaction with ozone is complete, as shown by the color of the reaction mixture, the ozonide intermediate is decomposed by the addition of a mild reducing agent such as dimethyl sulfide and triphenylphosphine to give the desired aldehyde of formula (XXXVa).

The preferred cis (4R, 6S) aldehydes of the formula (XXXVb) can be obtained from the corresponding racemic acids of the formula (XXXX) by customary separation processes, such as fractional crystallization after the introduction of a suitable salt-forming group. The resulting mixture of the diastereomeric salts, which is formed with an optically active salt-forming agent, we (1S, 2R) -Ephedrine and α- methylbenzylamine, is separated and the separated salts are converted into a compound of the formula (XXXVb). Fractional crystallization is preferably used as the salt-forming agent (1S, 2R) ephedrine and as the separation method. The dissolution (separation) takes place in an inert organic solvent and preferably in a mixture of hydrocarbon-alcohol solvents, e.g. B. a hexane-methanol mixture in which the separated salt crystallizes from the solution. If desired, the acid of the formula (XXXVb) can be converted into a salt, where R¹⁹ is a metal cation, or into a hydrolyzable ester group, where R¹⁹ is a C _1-4 alkyl group.

The most preferred antihypercholesterolemic Compounds of the formulas (XXXXIVa), (XXXXIVb) and (Ig) can one from a compound of the formula (XXXVa) or (XXXVb) according to the US application filed here and in the concurrent application described by William T. Han and John J. Wright general procedure. The use of aldehydes Formula (XXXVa) is shown in Reaction Scheme 15 while the use of the chiral aldehydes of the formula (XXXVb) in Reaction scheme 16 is explained.

In Reaction Schemes 15 and 16, R¹, R², R³, R⁴, R⁵, R⁶, R¹⁶, R¹⁷ and R¹⁹ as previously defined and Z represents

wherein R¹² represents a C _1-4 alkyl group, R¹³ represents a phenyl group which may be unsubstituted or substituted by one or two C _1-4 alkyl or chlorine radicals, and X represents bromine, chlorine or iodine. The preparation of the phosphonium salts of the formula (XVII) and the phosphonate salts of the formula (XVIIa) is described here in reaction scheme 13. The reaction of a compound of formula (XVII) or (XVIIa) with a compound of formula (XXXVa) or (XXXVb) to a compound of formula (XXXVII) or (XXXXIII), wherein R¹ R represents a C _1-4 alkyl group, can can be carried out in an inert organic solvent, such as tetrahydrofuran or N, N-dimethylformamide, in the presence of a strong base, such as n-butyllithium, at a temperature of about -50 ° C to about -78 ° C. When the reaction of a compound of formula (XVII) or (XVIIa) with a compound of formula (XXXVa) or (XXXVb) in which R¹⁹ represents a hydrogen atom, it is preferred to use two equivalents of a strong base such as n-butyllithium, to use. Alternatively, the salt of a compound of formula (XXXVa) or (XXXVb) can be prepared, which is then treated with a compound of formula (XVII) or (XVIIa) and a strong base. The methods of addition, salt formation and ylide production are known to the person skilled in the art. The protecting groups can easily be removed from the tetrazole compounds of the formulas (XXXXII) or (XXXXIII) by known methods, e.g. B. with a mild acid, such as 0.2N HCl and 0.5N HCl in an inert organic solvent, such as tetrahydrofuran, using the erythro compounds of the formula (XXXXIVa) or the (3R, 5S) compounds of the formula (XXXXIVb ) receives. These can then be converted into the trans compounds of the formula (Ig) or the (4R, 6S) compounds of the formula (Ig) in a conventional manner known to the person skilled in the art.

The invention also relates to the prodrug forms the preferred embodiment of the compounds of the formula (I) with the structure:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as previously defined, R²⁰ represents a hydrogen atom, a C _1-6 alkyl group or a metal cation and R²¹ is C _1-6 alkyl, hydroxy-C _1-6 alkyl, Phenyl-C _1-6 alkyl, hydroxyphenyl C _1-6 alkyl, amido C _1-6 alkyl, C _1-6 alkoxycarbonyl-C _1-6 alkyl, imidazol-4-yl-C _{1 -6-} alkyl, C _1-6 -alkylthio-C _1-6 -alkyl or indol-3-yl-C _1-6 -alkyl, the amido ester unit being in the L configuration.

In the compounds of formula (XXXXV), R¹, R², R³, R⁴, R⁵ and R⁶ independently of one another are preferably a hydrogen or halogen atom or a C _1-4 alkyl or C _1-4 alkoxy group. R¹ and R⁴ are particularly preferably hydrogen and R², R³, R⁵ and R⁶ independently of one another are hydrogen, fluorine, chlorine, methyl or methoxy. Most preferably R¹ and R⁴ represent a hydrogen atom and R², R³, R⁵ and R⁶ independently represent hydrogen, fluorine, methyl or methoxy. R²⁰ is preferably a hydrogen atom, a C _1-2 alkyl group or metal cation. R²¹ is preferably C _1-4 alkyl, hydroxy C _1-2 alkyl, phenyl C _1-2 alkyl, hydroxyphenyl C _1-2 alkyl, amido C _1-2 alkyl, C _1-2 -Alkoxycarbonyl-C _1-2 -alkyl, imidazol-4-yl-C _1-2 -alkyl, C _1-2 -alkylthio-C _1-2 -alkyl or indol-3-yl-C _1-2 -alkyl where the amido ester unit is in the L configuration. The preferred stereoisomer of formula (XXXXV), which has two asymmetric carbon atoms with the hydroxy groups in the 3- and 5-positions, is the erythro form, and the most preferred stereoisomer is the (3R, 5S) isomer of formula (XXXXV ).

The compounds of formula (XXXXV) are prodrugs of the invention Links. They become more systematic Administration in the body in useful antihyper transferred cholesterolemic agents. The most preferred Amino acid and amido ester derivatives of the formula (XXXXV) can be derived from the (4R, 6S) compounds of the formula (If) that described in US Pat. No. 4,678,806 and using the example of most preferred isomer discussed in Reaction Scheme 17 general procedure.

In the reaction scheme are R¹, R², R³, R⁴, R⁵, R⁶ and R²¹ as previously defined and R⁹ means a hydrolyzable Ester group. The compounds of the formula described here (If) can with an ester of a corresponding L- Amino acid in an inert organic solvent, such as Tetrahydrofuran, and preferably at the reflux temperature of Convert solvent to a compound of formula (XXXXVI). When making a compound of formula (XXXXV) is desired in which R²⁰ is a hydrogen atom or a metal cation means you can connect the Formula (XXXXV) under controlled conditions with diluted Alkali hydroxide such as sodium hydroxide and potassium hydroxide in the usual way to a compound of formula Hydrolyze (XXXXV).

The prodrug compounds according to the invention can be administered parenterally or preferably orally in the form of a capsule, tablet, as an injection or in a form like this for described other compounds according to the invention, administer. The oral dose unit contains the active ingredient in an amount of about 0.01 mg / kg to about 10 mg / kg body weight. It should be administered in equal doses 1 to 4 times a day will.

The compounds of formula (XXXXV) can also be used together with pharmaceutically acceptable non-toxic cationic Polymers are administered, which are able Bile acids in a non-reabsorbable form in the Bind gastrointestinal tract. For example, it is cholesterol, colestol and poly [methyl- (3- trimethylaminopropyl) iminotrimethylene dihalide]. The relative Amounts of polymers to compounds of the invention are between about 10: 1 to about 10,000: 1.

Description of specific embodiments

In the following examples, all temperatures are given in ° C. Melting points were recorded on a Thomas Hoover capillary melting point apparatus and boiling points were measured at specific pressures (mm Hg) and both temperature data are uncorrected. Proton magnetic resonance (1 H-NMR) spectra were recorded on a Bruker AM 300, Bruker WM 360 or Varian T-60 CW spectrometer. Unless otherwise stated, all spectra were recorded in CDCl₃, DMSO-d₆ or D₂O and chemical shifts are given in δ units, downfield from the internal standard tetramethylsilane (TMS) and interproton coupling constants are given in Hertz (Hz). Splitting patterns are identified as follows: s - singlet, d - doublet, t - triplet, q - quartet, m - multiplet, br - broad peak, and dd - doublet of a doublet. Carbon 13 nuclear magnetic resonance (13 C NMR) spectra were recorded on a Bruker Am 300 or Bruker WM 360 spectrometer and were broadband protons decoupled. If further information is missing, all spectra were recorded in CDCl₃, DMSO-d₆ or D₂O with an internal deuterium lock and chemical shifts are δ- unit depth shifted compared to TMS. Infrared (IR) spectra were recorded from 4000 cm ^-1 to 400 cm ^-1 on a Nicolet MX-1 FT spectrometer, calibrated for the 1601 cm ^-1 absorption of a polystyrene film, and in reciproken cm (cm ^-1 ) specified. Relative intensities are given as follows: s (strong), m (medium) and w (weak). Optical rotation values [ α ] were determined on a Perkin-Elmer 241 polarimeter in CHCl₃ at the concentrations indicated in each case.

Gas chromatography mass spectra (GC-MS) were on a Finnigan 4500 gas chromatography quadrupole mass spectrometer determined at an ionization potential of 70 eV.

Mass spectra were also recorded on a Kratos MS-50 instrument using the Fast atom bombardment (FAB) technique. The mass data are given as follows: molecular ion (M ^{+) or protenated ion (M + H) ⁺. Analytical thin layer chromatography (TLC) was carried out on pre-coated silica gel plates (60F-254) and visualized with the aid of UV light, iodine vapors and / or staining with one of the following reagents: (a) methanolic phosphomolybdic acid (2%) and heating; (b) Reagent (a) followed by 2% cobalt sulfate in 5M H₂SO₄ and heating. Column chromatography, also known as flash chromatography, was carried out in glass columns filled with finely powdered silica gel (32 to 63 μm silica gel-H), at pressures slightly above atmospheric pressure, using the solvents indicated. Ozonolysis was carried out using a Welsbach type T-23 ozonator. The solvents were always evaporated under reduced pressure. The term hexane (e) used herein, as specified by the American Chemical Society, denotes a mixture of isomers of C₆ hydrocarbons and the term inert atmosphere is an argon or nitrogen atmosphere unless otherwise stated.}

example 1 Ethyl 2-cyano-3,3-bis (4-fluorophenyl) -2-propanoate

A mixture of 20 g (92 mmol) of 4,4'-difluorobenzophenone and 11 g (97 mmol) of ethyl cyanoacetate in a solvent mixture of 100 ml of dry benzene and 20 ml of glacial acetic acid with a catalytic amount of β- alanine (0.9 g) was refluxed in a Dean-Stark trap with water removed. The water was separated rapidly during the first 2 h (0.4 ml aqueous phase was collected), then more slowly thereafter. The azeotropic distillation was continued for 14 days. Analytical TLC showed two points after elution with 10% EtOAc in hexane (v / v) (Merck plate, 0.25 mm silica gel-F) at R _f = 0.2 (desired product) and R _f = 0.45 (4th , 4′-difluorobenzophenones as starting material). The unpurified reaction mixture was washed with water (40 ml × 2) and the combined aqueous phases were extracted with EtOAc (150 ml × 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure, the product crystallizing out in whitish cubic crystals. The crude product was isolated, washed with 1: 1 EtOAc in hexane (v / v) and then recrystallized from 8: 1 hexane: ethyl acetate (v / v) to give 16.2 g (56.3%) of analytically pure title compound. Mp = 114-116 ° C.

IR (KBr) ν _max :
3000 (s), 2225 (s), 1931 (vs), 1605 (s), 1513 (s), 1250 (s), 844 (s) cm ^-1

1 H-NMR (CDCl₃) δ :
1.19 (3H, t, J = 7.1 Hz), 4.18 (2H, q, J = 7.1 Hz), 7.08-7.15 (6H, m), 7.40-7 , 42 (2H, m),

13 C NMR (CDCl 3) δ :
13.75; 62.27; 104.05; 116.69; 115.53 (d, ²J _CF = 22.7 Hz), 115.88 (d, ²J _CF = 22.7 Hz), 131.64 (d, ³J _CF = 9.1 Hz); 132.66 (d, 3 J _CF = 9.1 Hz); 134.25; 134.31; 134.36; 164.01 (d, 1 J _CF = 252.9 Hz), 164.52 (d, 1 J _CF = 254 Hz), 166.65 ppm

Elemental analysis for C₁₈H₁₃NO₂F₂:

calculated: C 69.01%; H 4.15%; N 4.47% found: C 68.91%; H 4.15%; N 4.62%

Example 2 Ethyl 3,3-bis (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate

5 g (16 mmol) of ethyl 2-cyano-3,3-bis (4-fluorophenyl) -2-propenoate is added to a dry 50 ml round-bottomed flask, followed by 8 g (24.1 mmol) of azidotributylstannate (prepared according to the Procedure as described in Rev. Trav. Chim., 81, 202-5 (1962)) and 2 ml of toluene (for synthesis). The heterogeneous mixture was stirred and heated under a protective glass in an oil bath under reflux (110 ° C.). The solid starting material gradually dissolves to form a slightly yellow, syrupy and homogeneous mixture which was stirred for 20 hours and refluxed. Analytical TLC with an eluent of 20% MeOH in CHCl₃ (v / v) showed the product at R _f = 0.26 (strip). The reaction mixture was diluted with an equal volume of diethyl ether and poured into a strongly stirred saturated aqueous solution of KF (containing 200 ml, 2 ml of 48% HBF₄). Shortly after mixing, a voluminous precipitate (Bu₃SnF) was observed and the hydrolysis was carried out for a further 16 h. The suspension was filtered and the filtrate was extracted with EtOAc (100 ml x 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. From the title compound, which crystallized out of the concentrate, 4.54 g (77%) were obtained in white, analytically pure form; FP = 159-161 ° C.

IR (KBr) _Max :
3438 (br), 1713 (vs), 1600 (s), 1510 (s), 1238 (s), 841 (s) cm^-1

1 H NMR (CDCl₃) δ :
0.92 (3H, t, J = 7.6 Hz), 3.98 (2H, q, J = 7.6 Hz), 7.3-6.7 (8H, m), 10 (1H, v . br.);

13 C NMR (CDCl 3) δ :
166.52; 163.54 (d, 1 J _CF = 250.7 Hz), 163.46 (d, 1 J _CF = 262.7 Hz); 157.14; 136.40; 134.74; 131.71 (d, ²J _CF = 67.2 Hz), 131.59 (d, ²J _CF = 66.4 Hz), 115.75 (d, ³J _CF = 18.9 Hz), 115.45 (d , ³J _CF = 18.1 Hz), 62.11; 13.47 ppm.

Elemental analysis for C₁₈H₁₄F₂N₄O₂:

calculated: C 60.27%; H 4.06%; N 15.50% found: C 60.67%; H 3.96%; N 15.72%

Example 3 Ethyl-3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenoate and ethyl 3,3-bis (4-fluorophenyl) -2- (2-methyl- 2H-tetrazol-5-yl) -2-propenoate A. Ethyl-3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazole- 5-yl) -2-propenoate

To a solution of 0.5 g (1.4 mmol) of ethyl 3,3-bis- (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate in 100 ml dried benzene, were at 45 ° C under argon 100 mg Sodium hydride (60% in mineral oil, 2.5 mmol) in one Portion added. The grayish suspension was at 45 ° C Stirred for 30 min, then 1 ml (16.1 mmol) of methyl iodide added and the flask was sealed with a rubber stopper. The alkylation was at 40 to 45 ° C over a Total duration of 4 days. Analytical TLC with eluent 20% EtOAc in hexane showed only two isomers Products at Rf = 0.16 (major isomer 4) and Rf = 0.22 (Minor isomer 5). The unpurified reaction mixture was washed with an equal volume of water and the aqueous Phases were back extracted 1 × with 50 ml diethyl ether. The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure, whereby the crude product was obtained. The product ratio of 1-isomer: 2-isomer was determined by gas chromatography and 1 H NMR spectroscopy determined to be about 5.6: 1.

The uncleaned one manufactured according to the above regulation Product mixture (5 g) was in 20 ml of hot ethyl acetate then 40 ml of hot hexane was added. The clear solution was allowed to cool slowly at room temperature, where 2.16 g (52%) of the title compound as a colorless long needles were obtained; Mp = 144-145 ° C.

Ir (KBr) _Max :
1713 (vs), 1600 (s), 1513 (s), 1325 (s), 1163 (s) ,, 838 (s) cm^-1

1 H-NMR (CDCl₃) δ :
7.4-6.8 (8H, m), 4.06 (2H, q, J = 7.1 Hz), 3.68 (3H, s), 1.00 (3H, t, J = 7, 1 Hz)

13 C NMR (CDCl 3) δ :
164.44; 163.6 (d, 1 J _CF = 250.7 Hz); 163.4 (d, 1 J _CF = 252.9 Hz); 156.85; 152.37; 135.88; 131.32 (d, 3 J _CF = 8.3 Hz); 115.94 (d, 2 J _CF = 21.9 Hz), 115.64 (d, 2 J _CF = 22.7 Hz); 61.84; 33.76; 13.59 ppm

Elemental analysis for C₁₉H₁₆F₂N₄O₂:

calculated: C 61.62%; H 4.35%; N 15.13% found: C 61.63%; H 4.45%; N 15.21%

B. Ethyl-3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazole- 5-yl) -2-propenoate

The filtration residue (2 g) from the recrystallization in stage A (approximately equal amounts of 1- and 2-methyl containing isomers) was over silica gel (35 g) chromatographed. The appropriate fractions were collected and evaporated to a crystalline product was obtained. Recrystallization from a mixture of Hexane / ethyl acetate (9: 1; v / v) gave the title compound. Mp = 117-118 ° C.

IR (KBr) _Max :
1713 (vs), 1600 (s), 1506 (s), 1250 (sh), 1225 (vs), 850 (m) cm^-1

1 H-NMR (CDCl₃) δ :
7.4-6.8 (8H, m), 4.20 (3H, s), 406 (2H, q, J = 7.1 Hz), 0.99 (3H, t, J = 7.1 Hz );

13 C NMR (CDCl 3) δ :
167.12; 163.02 (d, 1 J _CF = 272.6 Hz), 163.03 (d, 1 J _CF = 225.7 Hz); 162.8; 152.59; 137.03 (d, ⁴J _CF = 4 Hz); 135.96 (d, ⁴J _CF = 3 Hz); 131.94 (d, 3 J _CF = 8.3 Hz); 131.08 (d, 3 J _CF = 8.3 Hz), 120.48; 115.37 (d, ²J _CF = 21.9 Hz); 115.26 (d, ²J _CF = 22.7 Hz); 61.41; 39.40, 13.61 ppm

Elemental analysis for C₁₉H₁₆F₂N₄O₂:

calculated: C 61.62%; H 4.35%; N 15.13% found: C 61.77%; H 4.44%; N 15.38%

Example 4 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2- propenecarboxylic acid

To a solution of ethyl 3,3-bis (4-fluorophenyl) -2- (1-methyl- 1H-tetrazol-5-yl) -2-propenoate (4 g, 10.8 mmol) in one Mixture of 20 ml of methanol and 20 ml of tetrahydrofuran was at 0 ° C (ice water bath) a 3 molar aqueous lithium hydroxide solution (9 ml) added. The saponification reaction was over Performed overnight (approx. 16 h), with a homogeneous Solution made. Analytical TLC showed after two runs with 30% ethyl acetate in hexane (v / v) the desired product at the starting point. The unpurified reaction mixture was through Add 10 ml of 3 molar HCl solution acidified, then was the organic material twice with ethyl acetate (20 ml × 2) extracted. The organic phases were combined over MgSO₄ dried and concentrated under reduced pressure, leaving the product as a pale yellow solid. Crystallization from EtOAc-hexane (1: 9; v / v) gave 3.8 g (100) the title compound; Mp = 205-206 ° C.

IR (KBr) _Max :
3438 (br), 2900 (br), 1725 (s), 1713 (s), 1600 (s), 1501 (s), 1231 (vs), 1156 (s), 850 (s) cm^-1

1 H-NMR (CDCl₃) δ :
7.9-6.4 (8H, m); 3.68 (3H, s)

13 C NMR (CDCl 3) δ :
166.56; 163.3 (d, 1 J _CF = 249.9 Hz); 163.03 (d, 1 J _CF = 250 Hz); 155.68; 152.61; 135.58; 134.74; 131.75 (d, 3 J _CF = 8.3 Hz); 131.28 (d, 3 J _CF = 9.1 Hz); 117; 115.7 (d, ²J _CF = 22.6 Hz); 115.4 (d, ²J _CF = 22.6 Hz); 33.6 ppm.

Elemental analysis for C₁₇H₁₂F₂N₄O₂:

calculated: C 59.05%; H 3.53%; N 16.37% found: C 59.54%; H 3.58%; N 16.27%

Example 5 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2- propenecarboxylic acid

The general procedure of Example 4 was repeated with the exception that the ethyl 3,3-bis (4-fluorophenyl) used here 2- (1-methyl-1H-tetrazol-5-yl) -2-propenoate replaced was replaced by ethyl-3,3-bis (fluorophenyl) -2- (2-methyl-2H- tetrazol-5-yl) -2-propenoate, after recrystallization from ethyl acetate-hexane the title compound in 100% yield was obtained; Mp = 154-155 ° C.

IR (KBr) _Max :
3438 (br), 3000 (br), 1675 (s), 1600 (s), 1503 (y), 1231 (s), 1225 (s), 1150 (s), 838 (s) cm^-1

1 H-NMR (CDCl₃-DMSO-d₆) w :
7.33 - 7.28 (2H, m); 7.05-6.96 (4H, m), 6.87 (2H, t, J = 8.64 Hz); 4.23 (3H, s)

13 C-NMR (CDCl₃-DMSO-d₆) δ :
168.70; 163.05 (d, 1 J _CF = 248.4 Hz); 163.07; 162.66 (d, 1 J _CF = 249.9 Hz); 151.81; 136.81; 136.22; 131.83 (d, 3 J _CF = 8.3 Hz); 131.20 (d, 3 J _CF = 8.3 Hz); 121.04; 115.24 (d, ²J _CF = 21.9 Hz); 115.14 (d, ²J _CF = 21.1 Hz) ppm.

Elemental analysis for C₁₇H₁₂F₂N₄O₂:

calculated: C 59.65%; H 3.53%; N 16.37% found: C 59.56%; H 3.59%; N 16.36%

Example 6 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2- propenal A. 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2- propenyl chloride

To a solution of dried (0.1 mmHg at 80 ° C) 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2- propenecarboxylic acid 3.8 g (11 mmol) in 20 ml of dried Methylene chloride was purified 4 ml (46 mmol) Oxalyl chloride (redistilled over CaH₂) in one portion admitted. The reaction mixture was slowly warmed up and Heated at reflux for 2 h. The mixture was reduced Pressure evaporated to the volatile solvent then remove excess oxalyl chloride under vacuum (20 mmHg) at ambient temperature and a duration of 2 h and under high vacuum (0.1 mmHg) at 50 ° C and a duration of 16 h, after which the Title compound was obtained.

B. 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenol

The acyl chloride synthesized in stage A was dissolved in 150 ml of tetrahydrofuran and cooled to -78 ° C. under argon. 8 ml of lithium aluminum hydride in THF (1.0 molar) were added to this pale brown solution at -78 ° C. Analytical TLC showed only a mobile point at R _f = 0.23 (50% EtOAc in hexane v / v) after 15 min. The unpurified reaction mixture was diluted with 2M H₂SO₄ (20 ml). The aqueous phase was extracted with ethyl acetate (40 ml x 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure to give 3.64 g (100%) of the title compound. The allyl alcohol was immediately implemented in the next step without further purification. MS (CI): m / e = 328 for (M + H) ⁺;

IR (KBr) _Max :
3388 (v. Br), 1600 (s), 1501 (s), 1225 (s), 1156 (s), 838 (s), 750 (s) cm^-1

1 H-NMR (CDCl₃) δ :
7.5-6.9 (8H, m); 4.52 (2H, br); 3.42 (3H, s); 3.75 (1H, br, D₂O interchangeable);

1 H-NMR (DMSO-d₆) δ :
7.5-6.9 (8H, m), 5.23 (1H, t, J = 5.5 Hz), 4.27 (2H, d, J = 5.5 Hz); 354 (3H, s) ppm.

C. 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2- propenal

To a vigorously stirred solution of the unpurified allyl alcohol (3.64 g, shown in Step B) in 40 ml of methylene chloride, 2.6 g (12 mmol) of pyridinium chlorochromate were added in a single portion at room temperature. Immediately following analytical TLC showed about 50% product at R _f = 0.34 and the starting material at R _f = 0.14 (elution with 50% EtOAc: hexane v / v). The oxidation was carried out at room temperature for a total of 16 h, the entire starting material being consumed and TLC only showing the product. The unpurified reaction suspension was filtered through a bed of silica gel and washed with 1 liter of 10% (v / v) ethyl acetate in hexane and 1 liter of 20% (v / v) ethyl acetate in hexane. The desired product crystallized at the concentration under reduced pressure to obtain 2.7 g (74%) of the title compound. Mp = 141-142 ° C. (CI): m / e = 326 for (M + H) ⁺.

IR (KBr) _Max :
3075 (m), 2875 (m), 1675 (s), 1600 (s), 1501 (s), 1238 (s), 1156 (s), 850 (s), 750 (s) cm^-1.

1 H-NMR (CDCl₃) δ :
9.63 (1H, s), 9.5-6.9 (8H, m), 3.74 (3H, s),

13 C NMR (CDCl 3) δ :
188.93; 165.44; 164.88 (d, 1 J _CF = 254.4 Hz); 164.10 (d, 1 J _CF = 255.9 Hz); 151.34; 134.31; 133.77 (d, 3 J _CF = 8.3 Hz); 132.69; 132.23 (d, 3 J _CF = 7.5 Hz); 123.70; 116.26 (d, ²J _CF = 21.9 Hz); 116.18 (d, ²J _CF = 22.7 Hz); 34.10 ppm.

Elemental analysis for C₁₇H₁₂F₂N₄O:

calculated: C 62.58%; H 3.71%; N 17.17% found: C 62.41%; H 3.85%; N 16.98%

Example 7 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2- propenal

The general test procedure for stages A, B and C from Example 6 was repeated, the 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) used in stage A being used. 2-propenecarboxylic acid was replaced by 3,3-bis (4-fluorophenyl) -2- (2-methyl-2H-tetrazol-5-yl) -2-propenecarboxylic acid (prepared in Example 5), whereby the title compound as a rubbery solid in 76% yield was obtained. MS (CI): m / e = 326 for (M + H) ⁺

IR (KBr) _Max :
2863 (m), 2750 (w), 1681 (s), 1600 (s), 1503 (s), 1225 (s), 1156 (s), 838 (s), 752 (s) cm^-1

1 H-NMR (CDCl₃) w :
9.65; 7.34-7.30 (2H, m); 7.15 (2H, t, J = 8.5 Hz); 7.01-6.96 (2H, m); 6.88 (2H, t, J = 8.4 Hz); 4.29 (3H, s);

13 C NMR (CDCl 3) δ :
190.08; 164.30 (d, 1 J _CF = 254.4 Hz); 163.5 (d, 1 J _CF = 252.17 Hz); 163.20; 161.37; 135.55; 133.49; 133.66 (d, J _CF = 7.6 Hz); 132.38 (d, 3 J _CF = 9.1 Hz); 131.40; 127.54; 115.86 (d, ²J _CF = 26.4 Hz); 115.57 (d, ²J _CF = 28.7 Hz); 39.55 ppm.

Elemental analysis for C₁₇H₁₂F₂N₄O:

calculated: C 62.58%; H 3.71%; N 17.17% found: C 62.27%; H 4.22%; N 15.83%

Example 8 5,5-bis (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal-

To a dry mixture of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (0.70 g; 2.1 mmol) and triphenylphosphoranylidene acetaldehyde (0, 72 g; 2.5 mmol) 20 ml of dried benzene were added under argon and at room temperature. The suspension was heated to reflux under an argon atmosphere and the reaction was continued at reflux for 30 min. Analytical TLC showed only one point for the product after R 4 runs with 20% ethyl acetate in hexane (v / v) at R _f = 0.15. The crude product was applied to a silica gel column saturated with hexane. The desired product was eluted with 1.5 l of 20% EtOAc in hexane (v / v) and 0.67 g (89%) of the title compound homogeneous by TLC was obtained from the eluate.

1 H-NMR (CDCl₃) δ :
9.53 (1H, d, J = 7.5 Hz); 7.47 (1H, d, J = 15.7 Hz); 7.4-8.8 (m); 5.80 (1H, dd, J₁ = 7.4 Hz, J₂ = 15.7 Hz); 4.11 (2H, q, J = 7.1 Hz); 3.58 (3H, s); 1.26 (3H, t, J = 7.1 Hz) ppm.

Proton NMR (300 MHz) of the compound prepared above showed the content of approx. 10% 7,7-bis (4-fluorophenyl) - 6- (1-methyl-1H-tetrazol-5-yl) -2,4,6-heptatrienal, one difficult by-product to be removed. This material was used in the next synthesis used without further purification.

Example 9 5,5-bis (4-fluorophenyl) -4- (2-methyl-2H-tetrazol-5-yl) -2,4- pentadienal

The general experimental procedure of Example 8 was followed by repeated except that the 3,3-bis used therein (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal was replaced by 0.67 g (21 mmol) of 3,3-bis (4-fluorophenyl) - -2- (2-methyl-2H-tetrazol-5-yl) -2-propenal (made in example 7). The reaction was carried out with 0.64 g (21 mmol) triphenylphosphoranylidene acetaldehyde, whereby 0.66 g (90.5%) of the title compound were obtained.

1 H-NMR (CDCl₃) δ :
9.57 (1H, d, J = 6.8 Hz); 7.50 (1H, d, J = 16.5 Hz); 7.3-6.8 (8H, m); 5.94 (1H, dd, J = 6.8, 16.5 Hz); 4.30 (3H, s) ppm.

Example 10 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazole- 5-yl) -3-oxo-6,8-nonadienoate and ethyl 11,11-bis (4-fluorophenyl) - 5-hydroxy-10- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8,10- undecatrienoat A. Ethyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H- tetrazol-5-yl) -3-oxo-6,8-nonadienoate

To a cooled suspension (0 ° C, ice water bath) of NaH (0.64 g; 16 mmol) (60% in mineral oil) in 20 ml of dried tetrahydrofuran was added ethyl acetate (2.04 ml, 16 mmol) in four equal portions under argon admitted. The homogeneous clear solution was stirred at 0 ° C for 30 min, followed by the dropwise addition of 6.4 ml of 2.5 M n-BuLi (16 mmol) over a period of 15 min. The orange solution of the dianion was at 0 ° C stirred for a further h. The ice water bath was replaced by an acetone dry ice bath (-78 ° C.) and the dianion was cannulated into a tetrahydrofuran solution (20 ml) with 5,5-bis (4-fluorophenyl) -4- (1-methyl- 1H-tetrazol-5-yl) - 2,4-pentadienal (2.82 g, 8.01 mmol). Analytical TLC showed the desired main product at R _f = 0.15 (50% EtOAc in hexane) and a by-product at R _f = 0.2. The unpurified reaction mixture was diluted with 40 ml of 1N HCl, the aqueous phase was extracted with ethyl acetate (50 ml × 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. The desired product was purified by flash chromatography on silica gel (elution with 20% EtOAc in hexane (v / v) to give 2.26 g (58.5%) of the title compound. MS (CI): m / e = 483 for (M + H) ⁺

IR (KBr) _Max :
3459 (v. Br), 1738 (s); 1725 (s); 1606 (s); 1513 (vs); 1225 (s); 1163 (s); 844 (s) cm^-1;

1 H-NMR (CDCl₃) δ :
7.4-6.8 (8H, m); 6.72 (1H, d, J = 15.6 Hz); 4.63 (1H, m); 4.17 (2H, q, J = 7.1 Hz); 4.13 (1H, m); 3.60 (3H, s); 3.52 (1H, d, J = 3.9 Hz, D₂O interchangeable); 3.47 (2H, s); 2.74 (2H, d, J = 6 Hz); 1.26 (3H, t, J = 7.1 Hz) ppm;

13 C NMR (CDCl 3) δ :
164.21; 135.98; 132.34 (d, 3 J _CF = 8.3 Hz); 131.45 (d, 3 J _CF = 9.1 Hz); 115.74 (d, ²J _CF = 21.9 Hz); 115.74 (d, ²J _CF = 21.1 Hz); 100.86; 67.61; 61.58; 49.85; 49.07; 33.56, 14.10 ppm.

B. Ethyl-11,11-bis (4-fluorophenyl) -5-hydroxy-10- (1-methyl-1H- tetrazol-5-yl) -3-oxo-6,8,10-undecatrienoate

The silica gel column mentioned in step A was further eluted to obtain the by-product (R _f = 0.2). Flash chromatography again on silica gel with 20% EtOAc in hexane as eluent gave the title compound.

1 H-NMR (CDCl₃) δ :
7.4 - 7.1 (4H, m); 6.9-6.8 (4H, m); 6.58 (1H, d, J = 15.5 Hz); 6.31 (1H, dd, J = 10.7, 15.0 Hz); 5.80 (1H, dd, J = 10.7, 15.4 Hz); 5.66 (1H, dd, J = 5.5, 15.1 Hz); 4.64 (1H, m); 4.18 (2H, q, J = 6.9 Hz); 3.58 (3H, s); 3.46 (2H, s); 3.02 (1H, m); 2.75-2.72 (2H, m); 1.27 (3H, t, J = 6.9 Hz) ppm.

Example 11 Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

To a solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) 3-oxo-6,8-nonadienoate (2.19 g , 4.53 mmol) (dried in a high vacuum at 30 ° C, 48 h) in 40 ml of anhydrous tetrahydrofuran, a triethylborane solution in tetrahydrofuran (4.8 ml, 4.8 mmol) at 0 ° C (ice water bath) under argon added in one portion. The mixture was stirred under argon for 1 h. The ice water bath was replaced by an acetone dry ice bath, then NaBH₄ (0.20 g, 5.3 mmol) was added in one portion to the reaction mixture. The reaction suspension was stirred at -78 ° C. for 2 hours, a clear, homogeneous, pale yellow solution being formed. The unpurified reaction mixture was diluted with 40 ml 1N HCl and extracted with EtOAc 40 ml × 2). The organic layers were combined, dried over MgSO₄ and concentrated under reduced pressure to give the syrupy product, which was diluted with 300 ml of methanol. The solution was left to stand at room temperature for 16 hours and then evaporated under reduced pressure. The crude product was purified by flash chromatography on silica gel using 2 liters of 30% EtOAc in hexane as the eluent. The appropriate fractions were collected and evaporated to give 1.48 g (68%) of the title compound. MS (CI): m / e = 485 for (M + H) ⁺

IR (KBr) _Max :
3438 (s); 1734 (s); 1600 (s); 1513 (s); 1225 (s); 1163 (s); 844 (s) cm^-1;

1 H-NMR (DMSO-d₆) δ :
7.4-7.3 (4H, m); 7.04 (2H, t, J = 8.9 Hz); 6.9-6.7 (2H, m); 6.52 (1H, dd, J = 1; 15.2 Hz); 5.16 (1H, dd, J = 5.6, 15.7 Hz); 4.89 (1H, d, J = 4.8 Hz); 4.72 (1H, d, J = 5.5 Hz); 4.13 (1H, m); 4.04 (2H, q, J = 7.2 Hz); 3.85 (1H, m); 3.75 (3H, s); 2.42 (1H, dd, J = 4.6, 15 Hz); 2.28 (1H, dd, J = 8.3, 15 Hz); 5.5 (1H, m); 4.2 (1H, m); 1.17 (3H, t, J = 7.2 Hz);

13 C-NMR (DMSO-d₆) δ :
171.02; 163.51; 163.05; 153.03; 145.34; 139.46; 132.2 (d, 3 J _CF = 8.3 Hz); 131 (d, 13 J _CF = 9.1 Hz); 125.14; 121.64; 115.41 (d, ²J _CF = 20.4 Hz); 115.13 (d, ²J _CF = 21.1 Hz); 67.79; 64.76; 59.50; 44.10; 42.34; 33.44, 14.01 ppm.

Elemental analysis for C₂₅H₂₆F₂N₄O₄:

calculated: C 61.98%; H 5.41%; N 11.56% found: C 61.51%; H 5.67%; N 11.12%

Example 12 Sodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

To a solution of ethyl 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate (1.231 g; 2, 54 mmol) in 35 ml of tetrahydrofuran, a 1N NaOH solution (2.54 ml, 1 equivalent) was added dropwise at 0 ° C. The addition should take place so slowly that no color change to deep amber or reddish is observed in the reaction mixture. The reaction mixture was stirred at 0 ° C. for 30 minutes, a clear homogeneous solution being formed. The unpurified reaction mixture was warmed to room temperature and the saponification reaction was carried out for a further hour. Analytical TLC eluted with 20% MeOH in CHCl₃ (v / v) showed the desired product at R _f = 0.2. Most of the organic solvent was removed at about 10 ° C and reduced pressure (20 mm Hg). The resulting thick syrup was diluted with 4 ml of water and the solution was lyophilized at 0.01 mm Hg, 1.126 g (100%) of the title compound being obtained as the sodium salt containing about 1 mol of water. Mp <100 ° C (decomposition).

IR (KBr) _Max :
3400 (v. Br), 1600 (s), 1575 (s), 1513 (s), 1438 (s), 1404 (s), 1225 (s), 1156 (s), 838 (s) cm^-1;

1 H-NMR (DMSO-d₆) δ :
7.3-7.4 (4H, m); 7.06 (1H, br, D₂O interchangeable); 7.00 - 7.06 (2H, m); 6.87-6.91 (2H, m); 6.49 (1H, d, J = 15.7 Hz); 5.13 (1H, dd, J = 5.4, 15.7 Hz); 5.05 (1H, br, D₂O interchangeable); 4.14 (1H, m); 3.74 (3H, s); 3.62 (1H, m); 1.99 (1H, dd, J = 3.7, 13.5 Hz); 1.80 (1H, dd, J = 8.5, 13.5 Hz); 1.43 (1H, m); 1.30 (1H, m);

13 C-NMR (DMSO-d₆) w :
175.87; 161.85 (d, 1 J _CF = 246.1 Hz); 161.37 (d, 1 J _CF = 246.9 Hz); 153.08; 144.97; 139.88; 136.40; 135.51; 132.22 (d, 3 J _CF = 8.3 Hz); 130.97 (d, 3 J _CF = 8.3 Hz); 124.66; 121.74; 115.42 (d, ²J _CF = 21.9 Hz); 115.12 (d, ²J _CF = 23.4 Hz); 68.23; 65.71; 44.50; 43.55; 33.45 ppm.

Elemental analysis for C₂₃H₂₁F₂N₄O₄NaH₂O:

calculated: C 55.64%; H 4.67%; N 11.28% found: C 55.24%; H 4.65%; N 10.85%

Example 13 Trans-6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - 1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one A. (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid

To a solution of ethyl (±) -erythro-9,9-bis (4-fluorophenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6.8- nonadienoate (0.64 g, 132 mmol) in 25 ml of tetrahydrofuran 1.32 ml (1 molar) of NaOH solution were added at 0 ° C. The pale yellow suspension was stirred at 0 ° C. for 2 h, a clear pale yellow solution formed. The reaction mixture was washed with 5 ml aqueous HCl (2N) diluted and the organic material in ethyl acetate (40 ml x 2) extracted. The organic extracts were combined, dried over MgSO₄ and at reduced Pressure concentrated, leaving a pale yellow viscous residue was obtained. The unpurified dihydroxy acid was in a high vacuum (0.01 mm Hg at room temperature, 24 h) completely dried and then the next Step used.

B. trans-6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazole- 5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran 2-on

The dried acid from step A was dissolved in 100 ml of dried methylene chloride at room temperature and under argon and mixed with 1.7 g (4 mmol) of 1-cyclohexyl-3- (2-morpholinoethyl) carbodiimide-metho-p-toluenesulfonate . Analytical TLC (R _f = 0.12), eluted 3 × with 50% ethyl acetate in hexane, showed complete lactonization in less than 15 min. Most of the solvent was evaporated under reduced pressure and the residue was washed with 40 ml of water followed by extraction with ethyl acetate (40 ml x 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure to give 0.54 g (89.7%) of the product. A pure product could be obtained by elution from a short silica gel column with 40% ethyl acetate in hexane (v / v), the title compound containing about 2 moles of water. MS (CI): m / e = 438 for (M + H) ⁺.

IR (KBr) _Max :
3425 (br); 1738 (v.s); 1600 (s); 1513 (s); 1225 (vs); 1156 (s); 1038 (s); 838 (s) cm^-1;

1 H-NMR (CDCl₃) δ :
7.26-7.21 (2H, m); 7.14 (2H, d, J = 8.7 Hz); 6.86 (4H, d, J = 6.8 Hz); 6.72 (1H, dd, J = 0.8, 15.6 Hz); 5.34 (1H, dd, J = 7.1, 15.6 Hz); 5.18 (1H, m); 4.37 (1H, m); 3.57 (3H, s); 2.68 (1H, dd, J = 4.5, 18 Hz); 2.60 (1H, ddd, J = 3.63, 2.5, 18 Hz); 2.44 (1H, d, J = 2.6 H₂, D₂O interchangeable); 2.00 (1H, dt, J = 18, 1.7 Hz); 1.79 (1H, td, J = 2.7, 18 Hz) ppm;

13 C NMR (CDCl 3) δ :
169.20; 163; 162.5; 153.20; 148.81; 135.61; 134.95; 132.45 (d, 3 J _CF = 8 Hz); 132.52; 131.51 (d, 3 J _CF = 8 Hz); 130.04; 120.44; 115.95 (d, ²J _CF = 21.9 Hz); 115.83 (d, ²J _CF = 21.9 Hz); 75.67; 62.54; 38.58; 35.58; 33.64 ppm

Elemental analysis for C₂₃H₂₀F₂N₄O₃2H₂O:

calculated: C 58.22%; H 5.10%; N 11.81% found: C 59.06%; H 4.45%; N 11.25%

A sample of the lactone synthesized above was made from cyclohexane Recrystallized benzene, the title compound as crystalline solid containing about 1 mole of benzene originated; FP = 105-106 ° C.

Elemental analysis for C₂₃H₂₀F₂N₄O₃C₆H₆:

calculated: C 67.48%; H 5.07%; N 10.85% found: C 67.44%; H 5.23%; N 10.59%

Example 14 Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazol-5-yl) -6,8-nonadienoate A. Ethyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (2-methyl-2H- tetrazol-5-yl) -3-oxo-6,8-nonadienoate

The general experimental procedure of Example 10 Step A was repeated using the one used therein 5,5-bis (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal was replaced by 0.66 g (1.87 mmol) 5,5-bis (4-fluorophenyl) -4- (2-methyl-2H-tetrazol-5-yl) -2,4- pentadienal. After silica gel chromatography, one obtained 0.53 g (59%) of the title compound.

B. Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- (2-methyl-2H-tetrazol-5-yl) -6,8-nonadienoate

The product from step A was triethylborane and Sodium borohydride according to the general test instructions of Example 11, yielding 0.37 g (69.8%) of the title compound after purification by silica gel chromatography were formed.

1 H-NMR (CDCl₃) δ :
7.30-7.22 (2H, m); 7.07 (2H, t, J = 6.7 Hz); 6.89-6.86 (2H, m); 6.78 (2H, t, J = 8.7 Hz); 6.66 (1H, d, J = 15.5 Hz); 5.39 (1H, dd, J = 6.3, 15.5 Hz); 4.41 (1H, m); 4.2 (1H, m); 4.27 (3H, s); 4.18 (2H, q, J = 7.1 Hz); 3.92 (1H, br, D₂O interchangeable), 3.69 (1H, br, D₂O interchangeable); 2.47-2.42 (2H, m); 1.66-1.58 (2H, m); 1.26 (3H, t, J = 7.1 Hz)

13 C NMR (CDCl 3) δ :
172.29; 162.52 (d, 1 J _CF = 249.9 Hz); 161.94 (d, 1 J _CF = 248.4 Hz); 145.74; 137.59; 137.33; 136.87; 132.37 (d, 3 J _CF = 8.3 Hz); 131.69 (d, 3 J _CF = 8.3 Hz); 128.53; 124.90; 115.50 (d, ²J _CF = 21.1 Hz); 115.2 (d, ²J _CF = 20 Hz); 72.11; 68.07; 60.74; 42.52; 41.73; 39.42; 14.17 ppm.

Example 15 Ethyl- (±) -erythro-11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- (1-methyl-1H-tetrazol-5-yl) -6,8,10-undecatrienoate and Sodium (±) erythro-11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- (1-methyl-1H-tetrazol-5-yl) -6,8,10-undecatrienoate A. Ethyl- (±) -erythro-11,11-bis (4-fluorophenyl) -3,5-di hydroxy-10 (1-methyl-1H-tetrazol-5-yl) -6,8,10-undecatrienoate

The general experimental procedure of Example 11 was repeated, the ethyl 9,9-bis used therein (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 3-oxo-6,8-nonadienoate was replaced by 0.12 g Ethyl-11,11-bis (4-fluorophenyl) -5-hydroxy-10- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8,10-undecatrienoate (made in Example 10, step B), 50 mg (42%) obtained the title compound after silica gel chromatography were.

1 H-NMR (CDCl₃) δ :
7.4-6.8 (8H, m); 6.57 (1H, d, J = 15.4 Hz); 6.29 (1H, dd, J = 10.8, 15.1 Hz); 5.80 (1H, dd, J = 10.7, 15.4 Hz); 5.07 (1H, dd, J = 5.7, 15.1 Hz); 4.44 (1H, q, J = 5.8 Hz); 4.24 (1H, m); 4.16 (2H, q, J = 7.1 Hz); 3.83 (1H, br, D₂O interchangeable); 3.65 (1H, br, D₂O interchangeable); 3.58 (3H, s); 2.47 (2H, d, J = 6.3 Hz); 1.62 (2H, m); 1.28 (3H, t, J = 7.1 Hz);

13 C NMR (CDCl 3) δ :
172.43; 162.87 (d, 1 J _CF = 257.46 Hz); 162.47 (d, 1 J _CF = 249.91 Hz); 153.45; 146.20; 138.62; 135.98; 135.50; 133.98; 132.39 (d, 3 J _CF = 8.3 Hz); 131.48 (d, 3 J _CF = 8.3 Hz); 131.18; 129.80; 129.16; 121.95; 115.75 (d, ²J _CF = 22.0 Hz); 115.67 (d, ²J _CF = 22.0 Hz); 71.72; 68.34; 60.82; 42.45; 41.57; 33.54; 14.16 ppm;

B. Sodium (±) erythro-11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- (1-methyl-1H-tetrazol-5-yl) -6,8,10-undecatrienoate

The product from step A above was according to the general test instructions of example 12 saponified, the title compound being obtained in quantitative yield.

1 H-NMR (DMSO-d₆) δ :
7.5-6.8 (8H, m); 6.44 (1H, d, J = 15.5 Hz); 6.17 (1H, dd, J = 11.4, 14.8 Hz); 5.7 (2H, m); 4.14 (1H, q, J = 5.5 Hz); 3.7 (2H, br, D₂O interchangeable); 3.67 (3H, s); 3.90 (1H, m); 2.02 (1H, d, J = 11.7 Hz); 1.84 (1H, dd, J = 8.6, 14.4 Hz); 146 (1H, m); 1.29 (1H, m) ppm;

13 C-NMR (DMSO-d₆) δ :
176.12; 152.81; 141.50; 136.25; 135.62; 134.02; 132.35; 132.24; 127.72; 128.04; 122.17; 115.48 (d, ²J _CF = 21.9 Hz); 115.19 (d, ²J _CF = 21.1 Hz); 68.31; 44.59; 43.57; 33.40 ppm

Example 16 trans-6- [4,4-bis (4-fluorophenyl) -3- (2-methyl-2H-tetrazol-5-yl) - 1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one

The general experimental procedure of Example 13, Steps A and B, was repeated using the ethyl (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl) used therein -1H-tetrazol-5-yl) -6,8-nonadienoate was replaced by 370 mg of ethyl 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazole- 5-yl) -6,8-nonadienoate and 146 mg (44%) of the title compound were obtained after silica gel chromatography. MS (CI): m / e = 439 for (M + H) ⁺;

IR (KBr) _Max :
3438 (v. Br), 1731 (s), 1600 (s), 1503 (vs), 1219 (vs), 1153 (s), 1056 (m), 1031 (m), 838 (s) cm^-1;

1 H-NMR (CDCl₃) δ :
7.29-6.82 (8H, m); 6.69 (1H, d, J = 15.6 Hz); 5.44 (1H, dd, J = 9.0, 15.6 Hz); 5.24 (1H, m); 4.27 (3H, s); 4.30 (1H, m); 4.21 (1H, s, D₂O interchangeable); 3.69 (1H, br.s D₂O interchangeable); 2.6-2.4 (2H, m); 2.1-1.7 (2H, m);

13 C NMR (CDCl 3) δ :
169.94; 162.70 (d, 1 J _CF = 249.2 Hz); 162.12 (d, 1 J _CF = 249.9 Hz); 147.68; 147.47; 137.27; 136.11; 132.36 (d, 3 J _CF = 8.3 Hz); 131.71 (d, 3 J _CF = 8.3 Hz); 131.17; 131.10; 130.88; 128.62; 124.28; 11.52 (d, ²J _CF = 20.4 Hz); 114.95 (d, ²J _CF = 21.9 Hz), 76.16; 52.33; 39.49; 38.66; 35.99 ppm.

Elemental analysis for C₂₃H₂₀F₂N₄O₃ 2H₂O:

calculated: C 58.22%; H 5.10%; N 11.81% found: C 58.92%; H 4.62%; N 11.21%

Example 17 Sodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- (2-methyl-2H-tetrazol-5-yl) 6,8-nonadienoate

The general experimental procedure of Example 12 was repeated, the ethyl (±) erythro- 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole- 5-yl) -6,8-nonadienoate was replaced by ethyl 9,9- bis (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-1H-tetrazole- 5-yl) -6,8-nonadienoate and after lyophilization in quantitative yield of the title compound as sodium salt was obtained with a content of about 1 mole of water.

IR (KBr) _Max :
3413 (v.br); 1600 (s), 1575 (s), 1500 (s), 1400 (s), 1219 (s), 1088 (s) cm^-1;

1 H-NMR (DMSO-d₆) w :
7.36-6.82 (8H, m); 6.50 (1H, d, J = 15.5 Hz); 5.28 (1H, dd, J = 5.8, 15.5 Hz); 5.0 (1H, br, D₂O interchangeable); 4.9 (1H, br, D₂O interchangeable); 4.28 (3H, s); 4.13 (1H, d, J = 5.94 Hz); 3.64 (1H, m); 2.03 (1H, dd, J = 3.6, 14.9 Hz); 1.85 (1H, dd, J = 8.7, 14.9 Hz); 1.5-1.2 (2H, m);

13 C-NMR (DMSO-d₆) δ :
176.25; 103.18; 161.47 (d, 1 J _CF = 240 Hz); 143.15; 137.60; 136.40; 125.48; 115.12; 114.46; 68.52; 65.84; 44.61, 43.55 ppm.

Elemental analysis for C₂₃H₂₁F₂N₄O₄Na H₂O:

calculated: C 55.64%; H 4.67%; N 11.29% found: C 55.22%; H 4.79%; N 11.21%

Example 18 Phenylmethyl-9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate

3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) prop-2-enal (2.50 g; 7.7 mmol), phenylmethyl-6- (dimethylphosphono ) - 3-hydroxy-5-oxohexanoate (3.93 g; 11 mml) and anhydrous lithium bromide (1.4 g) were combined in acetonitrile and mixed with 1,8-diazobicyclo- [5.4.0] undec-7-ene ( 1.2 ml, 8 mmol) was added. The mixture was stirred under argon at 23 ° C for 44 h and then concentrated in vacuo. The residue was distributed in CH₂Cl₂ (50 ml) and ice-cold H₃PO₄ (100 ml). The organic phase was washed 2 × with water (2 × 50 ml), dried over anhydrous Na₂SO₄ and evaporated to give 4.2 g of an orange foam. The crude product was pre-adsorbed onto silica gel and flash chromatographed 3 × on a silica gel (10-40) column with 40% ethyl acetate / hexane as eluent to give 0.36 g of the title compound. MS (CI): m / e = 545 for (M + H) ⁺;

IR (KBr) _Max :
3449 (OH); 1735 cm^-1 (C (= O) OCH₂);

1 H-NMR (CDCl₃) δ :
2.50 (d, 2H, C-2 or C-4 CH₂, J = 6.2); 2.63 (d, 2H, C-2 or C-4 CH₂, J = 5.9); 3.33 (s, 1H, OH); 3.50 (s, 3H, NCH₃); 4.42 (m, 1H, CHOH); 5.09 (s, 2H, -OCH₂); 5.80 (d, 1H, C-5 olefin H, J = 16); 6.85-7.34 (m, 13H, ArH); 7.52 (d, 1H, C-7 olefin H, J = 16).

Example 19 Sodium (±) -9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl-1H- tetrazol-5-yl) -5-oxo-6,8-nonadienoate

Phenylmethyl-9,9-bis (4-fluorophenyl) -3-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -5-oxo-6,8-nonadienoate (0.34 g, 0.62 mmol) was dissolved in tetrahydrofuran (4 ml) and water (1 ml). 1N sodium hydroxide (0.62 ml, 0.62 mmol) was added and the solution thus obtained was stirred at 24 ° C. for 6 h. The mixture was diluted with water (10 ml) and with diethyl ether (3 × 50 ml) washed. The aqueous phase was lyophilized and 0.17 g (52%) of the title compound was obtained. Mp = 166-180 ° C (decomposition).

IR (KBr) _Max :
1585 cm^-1 (COO^-);

1 H-NMR (DMSO-d₆) δ :
1.76 (dd, 1H, C-4 CH, J = 8.4, 16); 1.97 (dd, 1H, C-4 CH, J = 3.6, 16); 2.42 (m, 1H, C-2 CH₂); 3.71 (s, 3H, NCH₃), 3.93 (m, 1H, CHOH); 5.80 (d, 1H, C-7 olefin-H, J = 16); 7.38-7.41 (m, 4H, ArH).

Elemental analysis for C₂₃H₁₉F₂N₄O₄Na 3.5 H₂O:

calculated: C 51.21%; H 4.86%; N 10.39% found: C 51.44%; H 3.97%; N 9.46%

Example 20 Ethyl-3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenoate and ethyl 3,3-bis (4-fluorophenyl) -2- [2- (1- methylethyl) -2H-tetrazol-5-yl] -2-propenoate A. Ethyl-3,3-bis (4-fluorophenyl) -2- [2- (1-methylethyl) -2H- tetrazol-5-yl] -2-propenoate

To a cooled (-78 ° C, dry ice / acetone) solution of ethyl 3,3-bis (5-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate (2.6 g; 7 , 3 mmol) (prepared in Example 2) in 20 ml of dried N, N-dimethylformamide was reacted under argon NaH (0.44 g, 11 mmol; 60% in mineral oil) followed by ²-iodopropane (2 ml, 20 mmol, reagent just added) in one portion. The viscous reaction mixture was stirred under argon at -78 ° C for 30 min. The reaction mixture was slowly warmed to room temperature over a period of 16 h. Analytical TLC, eluted 1 × with 50% ethyl acetate in hexane, showed only one point at R _f = 0.86. The white suspension was diluted with 40 ml of semi-saturated saline followed by 20 ml of ethyl acetate. The aqueous phase was washed with ethyl acetate (2 x 20 ml). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. Analytical TLC, eluted 4 × with 8% (v / v) ethyl acetate in hexane, showed two compounds at R _f = 0.38 (21) and R _f = 0.49 (21a). The desired products were purified by silica gel chromatography (elution with 8% EtOAc in hexane). The faster running product was collected to give 1.64 g (56.5%) of the title compound. MS (CI): m / e = 399 for (M + H) ⁺;

1 H-NMR (CDCl₃) δ :
7.29-6.85 (8H, m), 4.94 (1H, heptette, J = 6.7 Hz), 4.09 (2H, q, J = 6.9 Hz), 1.50 (6H , d, J = 6.8 Hz), 1.01 (3H, t, J = 6.9 Hz);

13 C NMR (CDCl 3) δ :
167.04, 163.20 (d, 1 J _CF = 248.4 Hz), 162.82 (d, 1 J _CF = 240 Hz), 152.65, 136.85, 136.19, 131.83 (d, 3 J _CF = 8.3 Hz), 131.04 (d, 3 J _CF = 8.3 Hz), 115.97, 115.85, 115.34 (d, 2 J _CF = 21.9 Hz), 115.11 (d, ²J _CF = 21.9 Hz), 61.38, 56.48, 22.04, 13.68 ppm.

B. Ethyl-3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H- tetrazol-5-yl] -2-propenoate

The silica gel column from Step A above was further eluted with 8% EtOAc in hexane to give the slower migrating product (R _f = 0.38). The appropriate fractions were combined and 0.95 g (32.7%) of the title compound was isolated therefrom. MS (CI): m / e = 399 for (M + H) ⁺;

1 H-NMR (CDCl₃) δ :
7.25-6.85 (8H, m), 4.30 (1H, heptette, J = 6.8 Hz), 4.04 (2H, q, J = 7.1 Hz), 1.26 (6H , d, J = 6.8 Hz), 1.01 (3H, t, J = 7.1 Hz);

13 C NMR (CDCl 3) δ :
165.6, 162.7 (d, 1 J _CF = 200 Hz), 155.7, 135.8, 134.2, 132.1 (d, 3 J _CF = 8.3 Hz), 131 (d, 3 J _CF) = 6.8 Hz), 115.8 (d, ²J _CF = 21.9 Hz), 115.7 (d, ²J _CF = 21.9 Hz), 61.81, 51.07, 22.18, 13 , 61 ppm.

Example 21 3,3-bis- (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenal A. 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenecarboxylic acid

To a chilled (0 ° C) solution of ethyl 3,3-bis (4- fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2- propenoate (0.95 g, 2.39 mmol) in 20 ml of a 1: 1 (v / v) Mixtures of tetrahydrofuran and methanol became one Solution of LiOH (4 ml, 3 molar) in one portion admitted. The reaction mixture was at 0 ° C for 15 min. stirred and then warmed to room temperature. The saponification took place in one at room temperature Period of 4 h with a whitish clear Solution. The unpurified reaction mixture was mixed with 12 ml Diluted 2M H₂SO₄ and the product in diethyl ether (40 ml × 2) extracted. The organic phases were combined dried over MgSO₄, concentrated under reduced pressure and in a high vacuum (0.01 mmHg) at room temperature above intensively dried for a period of 24 h, the Title compound was obtained. The propenecarboxylic acid was then in the next step without further purification used.

B. 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenol chloride

To a solution of the dried ones synthesized in step A. Acid in 20 ml of dried methylene chloride became 4 ml Oxalyl chloride (redistilled over CaH₂) at room temperature admitted. The mixture was argon for 2 h heated to reflux, with a slightly brownish Solution made. Much of the volatile solvent was evaporated at reduced pressure while last traces of oxalyl chloride in high vacuum (0.01 mmHg) were removed at room temperature in 12 h, after which the Title compound was obtained.

C. 3,3-bis (4-fluorophenyl) -2 [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenol

The acid chloride from step B was dissolved in 20 ml of dried tetrahydrofuran and reacted with the slow addition of 1.8 ml of lithium aluminum hydride (1.0 molar in tetrahydrofuran) at -78 ° C. and an argon atmosphere. Analytical TLC, eluted once with 30% EtOAc in hexane (v / v), showed the alcohol at R _f = 0.46. The untreated reaction mixture was poured into dilute H₂SO₄ (2N in H₂O) and the desired product was extracted with 3 volumes of diethyl ether (40 ml × 3). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. The yield of the title compound was 1.07 g and was used in the next reaction step without further purification.

D. 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenal

The alkyl alcohol (0.96 g) synthesized in stage C was dissolved in 45 ml of dried methylene chloride at room temperature and 0.64 g (2.96 mmol) of pyridinium chlorochromate was added in one portion with vigorous stirring. After the reaction mixture was stirred for 4 h, analytical TLC (single elution with 10% EtOAc in hexane (v / v) and two times elution with 20% EtOAc in hexane (v / v) showed a major product at R _f = 0.22 The unpurified mixture was applied to a silica gel bed (1.3 to 2.5 cm thick) and eluted with 20% EtOAc in hexane to give 0.51 g (53%) of the title compound. MS (CI): m / e = 335 for (M + H) ⁺;

Example 22 3,3-bis (4-fluorophenyl) -2- [2- (1-methylethyl) -2H-tetrazol-5-yl] - -2-propenal

The general test procedure of Example 21, stage A, B, C and D were repeated using the one used therein Ethyl-3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2-propenoate was replaced by ethyl 3,3-bis- (4-fluoro- phenyl) -2- [2- (1-methylethyl) -2H-tetrazol-5-yl] -2-propenoate. The yield of the title compound was 88%.

Example 23 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) - 1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate and ethyl 11,11-bis- (4-fluorophenyl) -5-hydroxy-10- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -3-oxo-6,8,10-undecatrienoate A. 5,5-bis (4-fluorophenyl) -4- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -2,4-pentadienal and 7,7-bis (4-fluorophenyl) -6- [1- (1- methylethyl) -1H-tetrazol-5-yl] -2,4,6-heptatrienal

To a dry mixture of 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2-propenal (0.51 g, 1.4 mmol) and triphenylphosphoranylidene acetaldehyde (0.48 g, 1.6 mmol) were added at room temperature and under argon 24 ml of dried benzene. The slightly brownish suspension was heated to about 120 ° C. in an oil bath with vigorous stirring. The mixture was quickly warmed and refluxed overnight (approx. 16 h). Analytical TLC of the brownish solution (5 × eluted with 20% EtOAc in hexane (v / v)) showed a point at R _f = 0.26; no traces of the starting aldehyde were found. The unpurified reaction mixture was chromatographed on a silica gel column and eluted with about 1 liter of 25% EtOAc in hexane (v / v). The corresponding fractions contained 0.54 g (99%) of a mixture of the title compounds (homogeneous on TLC). This material was used in the next step without further cleaning.

B. Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8 [1- (1-methyl- ethyl) -1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate and Ethyl 11,11-bis (4-fluorophenyl) -5-hydroxy-10- [1- (1-methyl- ethyl) -1H-tetrazol-5-yl] -3-oxo-6,8,10-undecatrienoate

The dianion of ethyl acetoacetate (0.36 ml, 2.8 mmol) in tetrahydrofuran (2.5 ml) was purified according to the procedure of Example 10 using NaH (0.11 g; 2.8 mmol) (60% in mineral oil ) and 2.5M n-BuLi in hexane (1.2 ml, 3 mmol) at 0 ° C under argon. After cooling to -78 ° C., the solution of the dianion was cannulated into a tetrahydrofuran solution (5 ml) at -78 ° C. and contained 0.52 g (1.4 mmol) of the dienal and trienal compounds from the step A convicted. The reaction mixture was stirred at -78 ° C and an argon atmosphere for 15 min. After elution twice with 50% EtOAc in hexane, analytical TLC predominantly showed a point at R _f = 0.41 and a secondary component at R _f = 0.47. The slightly brownish reaction mixture was diluted with 5 ml of 2M H₂SO₄ and extracted with EtOAc (40 ml × 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. The products were purified and chromatographed on silica gel (elution with 20% EtOAc in hexane (v / v) isolated. The corresponding fractions with R _f = 0.41 were combined and, after evaporation, 0.29 g (41%) of the title compound ethyl- 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate exploited therefrom.

1 H NMR (CDCl₃) δ :
7.29-7.25 (2H, m), 7.12 (2H, t, J = 8.64 Hz), 6.93-6.81 (4H, m), 6.75 (1H, d, J = 15.5 Hz), 5.27 (1H, dd, J = 5.64, 15.5 Hz), 4.62 (1H, br.q, J = 5.7 Hz), 4.29 ( 1H, heptet, J = 6.6 Hz), 4.17 (2H, q, J = 9.1 Hz), 3.46 (2H, br.s), 2.72 (2H, d, J = 6 Hz), 1.26 (3H, t, J = 9.1 Hz), 1.3-1.2 (6H, br. Peak) ppm.

The corresponding fractions with R _f = 0.47 were combined and, after evaporation, 0.13 g (17.3%) of the title compound ethyl 11,11-bis (4-fluorophenyl) -5-hydroxy-10- [1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6,8,10-undecatrienoate.

1 H NMR (CDCl₃) δ :
7.29-7.22 (2H, m), 7.20-7.10 (2H, m), 6.91-6.80 (4H, m), 6.59 (1H, d, J = 15 , 4 Hz), 6.29 (1H, dd, J = 10.7, 15.2 Hz), 5.70 (1H, dd, J = 10.7, 15.4 Hz), 5.84 (1H , dd, J = 9.9, 15.5 Hz), 4.62 (2H, br), 4.27 (1H, heptett, J = 6.6 Hz), 4.17 (2H, q, J = 7 Hz), 3.46 (2H, s), 3.1 (1H, br, D₂O interchangeable), 2.75-2.69 (2H, m), 1.26 (3H, t, J = 7 Hz ), 1.38-1.05 (6H, br. Peaks, restricted rotation of the isopropyl group) ppm.

Example 24 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (1-methylethyl) -2H-tetrazole- 5-yl] -3-oxo-6,8-nonadienoate and ethyl 7,7-bis (4-fluorophenyl) -5- hydroxy-6- [2- (1-methylethyl) -2H-tetrazol-5-yl] -3-oxo-6-heptenoate

The general experimental procedure of Example 23, Step A was repeated, the 3,3-bis (4-fluorophenyl) -2- [1- (1-methylethyl) -1H-tetrazol-5-yl] -2 used therein -propenal was replaced by 3,3-bis (4-fluorophenyl) -2- [2- (1-methylethyl) -2H-tetrazol-5-yl] -2-propenal and predominantly 5,5-bis (4th -fluorophenyl) -4- [2- (1-methylethyl) -2H-tetrazol-5-yl] - 2,4-pentadienal was obtained in 82% yield; MS (CI): m / e = 381 for (M + H) ⁺. This product was then reacted according to the general instructions of Example 23, stage B, ethyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (1-methylethyl) -2H-tetrazole- 5-yl] -3-oxo-6,8-nonadienoate with a low content of non-separable ethyl 7,7-bis (4-fluorophenyl) -5-hydroxy-6- [2- (1-methylethyl) - 2H-tetrazol-5-yl] -3-oxo-6-heptenoate was obtained in 69.7% yield.

1 H NMR (CDCl₃) δ :
7.31-7.11 (2H, m), 7.10-7.04 (2H, m) 6.91-6.78 (4H, m), 6.72 (1H, d, J = 15, 5 Hz), 5.46 (1H, dd, J = 5.91, 15.7 Hz), 4.95 (1H, Heptett J = 6.8 Hz), 4.64 (1H, br.S), 4.17 (2H, q, J = 7.2 Hz), 3.46 (2H, s), 2.75-2.72 (2H, m), 1.49 (6H, d, J = 6, 8 Hz), 1.28 (3H, t, J = 7.2 Hz) ppm.

Example 25 Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -6,8-nonadienoate

A solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate ( 0.29 g, 0.57 mmol) in 6 ml of dried tetrahydrofuran was added at 0 ° C (ice water bath) under argon with 0.65 ml of triethylborane in tetrahydrofuran (1.0 molar solution). The reaction mixture was stirred at -5 ° C to 0 ° C for 1 h before it was then cooled to -78 ° C (dry ice / acetone bath) under argon. Solid sodium borohydride (25 mg, 0.66 mmol) was added to this pale yellow solution and the reduction was carried out at -78 ° C. over a period of 2 h. The reduction was accelerated by adding 25 µl of absolute CH₃OH. After another h, an analytical TLC, once eluted with 1: 1 (v / v) EtOAc in hexane, showed complete conversion of the starting material. The cold reaction mixture was diluted with 20 ml 1M H₂SO₄ and the organic material extracted into EtOAc (40 ml × 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure, a pale yellow syrupy residue being obtained. This was dissolved in 200 ml of MeOH and the solution was left to stand at room temperature overnight. Analytical TLC eluted twice with 50% EtOAc in hexane showed a major product at R _f = 0.32. Purification on silica gel column chromatography using 30% (v / v) EtOAc in hexane gave a yield of 0.23 g (79%) of the title compound.

IR (KBr) _Max :
3438 (v.br), 1731 (s), 1600 (s), 1503 (s), 1225 (s), 1156 (s), 838 (s), 750 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.29-7.25 (2H, m), 7.12 (2H, t, J = 8.6 Hz), 6.61-6.93 (4H, m), 6.73 (1H, d, J = 15.8 Hz), 5.25 (1H, dd, J = 15.8, 6.5 Hz), 4.42 (1H, q, J = 5 Hz), 4.30 (1H, heptette, J = 6.7 Hz), 4.22 (1H, m), 4.22 (2H, vbr. D₂O interchangeable), 4.16 (2H, q, J = 7.2 Hz), 2.47 -2.45 (2H, m), 1.59-1.57 (2H, m), 1.26 (3H, t, J = 7.2 Hz), 1.4-1.0 (6H, br , disabled rotation of the isopropyl group);

13 C NMR (CDCl 3) δ :
172.26, 162.8 (d, ¹J _CF = 250.7 Hz), 162.41 (d, ¹J _CF = 250.7 Hz), 152.10, 146.19, 138.44, 137.88, 135.98, 135.40, 132.32 (d, ³J _CF = 8.3 Hz), 131.72 (d, ³J _CF = 8.3 Hz), 127.61, 121.81, 115.71 ( d, ²J _CF = 21.1 Hz), 115.48 (d, ²J _CF = 21.1 Hz), 71.63, 68.20, 60.77, 50.78, 42.29, 41.68, 24-20 (v. Br isopropyl signal due to restricted rotation), 14.14 ppm;

Elemental analysis for C₂₇H₃₀F₂N₄O₄:

calculated: C 59.11%; H 6.25%; N 10.21% found: C 60.40%; H 5.66%; N 9.91%

Example 26 Ethyl- (±) -erythro-11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- [1- (1-methylethyl) -1H-tetrazol-5-yl] -6,8,10-undecatrienoate

The general experimental procedure of Example 25 was repeated, the ethyl 9,9-bis (4- fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] - 3-oxo-6,8-nonadienoate was replaced by ethyl 11,11-bis- (4-fluorophenyl) -5-hydroxy-10- [1- (1-methylethyl) -1H-tetrazole- 5-yl] -3-oxo-6,8,10-undecatrienoate (0.13 g, 0.24 mmol) and 140 mg of the title compound were exploited.

1 H NMR (CDCl₃) δ :
7.29-7.22 (2H, m), 7.13 (2H, t, J = 8.6 Hz), 6.92-6.80 (4H, m), 6.58 (1H, d, J = 15.4 Hz), 6.27 (1H, dd, J = 10.7, 15.1 Hz), 5.70 (1H, dd, J = 10.6 15.5 Hz), 5.66 (1H, dd, J = 5.8, 15.4 Hz), 4.43 (1H, q, J = 6 Hz), 4.27 (1H, Heptett, J = 6.5 Hz), 4.24 (1H, m), 4.15 (2H, q, J = 7.2 Hz), 3.91 (1H, br, D₂O interchangeable), 3.78 (1H, br, D₂O interchangeable), 2.48- 2.43 (2H, m) 1.65-1.58 (2H, m), 1.42-1.32 and 0.97-0.67 (from br. Bands for isopropyl signals), 1.26 ( 3H, t, J = 7.2 Hz) ppm.

Example 27 Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- [2- (1-methylethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate and Ethyl- (±) -erythro-7,7-bis (4-fluorophenyl) -3,5-dihydroxy-6- [2- (1-methylethyl) -2H-tetrazol-5-yl] -6-heptenoate

The general test specification of Example 25 was repeated, the ethyl 9,9-bis- (4-fluorophenyl) -5-hydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] - 3-oxo-6,8-nonadienoate was replaced by ethyl 9,9- bis (4-fluorophenyl) -5-hydroxy-8- [2- (1-methylethyl) -2H-tetrazol-5-yl] - 3-oxo-6,8-nonadienoate containing ethyl 7,7- bis (4-fluorophenyl) -5-hydroxy-6- [2- (1-methylethyl) -2H-tetrazole- 5-yl] -3-oxo-6-heptenoate (prepared in Example 24). The reaction mixture became after silica gel chromatography the title compounds in 53% and 38% yield respectively receive.

1 H NMR (CDCl₃) δ :
7.28-7.23 (2H, m), 7.07 (2H, t, J = 8.6 Hz), 6.86-6.71 (4H, m) 6.66 (1H, d, J = 15.7 Hz), 5.45 (1H, dd, J = 6.4, 15.8 Hz), 4.95 (1H, heptette, J = 6.7 Hz), 4.43 (1H, br ), 4.22 (1H, br) 4.16 (2H, q, J = 7.2 Hz), 3.90 (1H, br, D₂O interchangeable), 3.64 (1H, br, D₂O interchangeable), 2.47-2.43 (2H, m), 1.67-1.60 (2H, m), 1.48 (6H, d, J = 6.7 Hz), 1.25 (3H, t, J = 7.2 Hz);

13 C NMR (CDCl 3) w :
172.32, 163.77, 162.53 (d, 1 J _CF = 248.4 Hz), 161.86 (d, 1 J _CF = 247.6 Hz), 145.61, 137.88, 137.05, 136.28, 132.38 (d, ³J _CF = 8.3 Hz), 131.64 (d, ³J _CF = 8.3 Hz), 131.19, 131.08, 128.36, 125.42, 115.58, (d, ²J _CF = 21.9 Hz), 114, 67 (d, ²J _CF = 21.9 Hz), 72.15, 68.08, 60.74, 56.41, 42.54 , 41.73, 22.04, 14.17 ppm and

1 H NMR (CDCl₃) δ :
7.30-7.26 (2H, m), 7.07 (2H, t, J = 8.6 Hz), 6.94-6.70 (2H, m), 6.83-6.77 ( 2H, m), 4.92 1H, heptette, J = 6.7 Hz), 4.24 (1H, m), 4.92 (1H, m, methine proton opposite to one of the hydroxy groups 4.14 (2H, q , J = 7.1 Hz), 4.00 (1H, d, J = 6.5 Hz, D₂O interchangeable), 3.54 (1H, d, J = 2.5 Hz), 2.45-2, 42 (2H, m), 1.85 (2H, t, J = 6.1 Hz), 1.48 (3H, d, J = 6.8 Hz), 1.47 (3H, d, J = 6 , 8 Hz), 1.25 (3H, t, J = 7.1 Hz),

13 C NMR (CDCl 3) δ :
172.18, 162.91, 162.51 (d, ¹J _CF = 248.4 Hz), 162.00 (d, ¹J _CF = 246.9 Hz), 146.44, 137.33, 135.98, 131.26 (d, 3 J _CF = 8.3 Hz), 131.19 (d, 1 J _CF = 8.3 Hz), 128.33, 115.52 (d, 2 J _CF = 21.1 Hz), 114 , 73 (d, ²J _CF = 21.9 Hz), 71.31, 67.77, 60.65, 56.50, 41.85, 41.45, 21.98, 14.18 ppm;

Example 28 Sodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- [1- (1-methylethyl) -1H-tetrazol-5-yl] -6,8-nonadienoate

To a solution of ethyl (±) -erythro-9,9-bis (4-fluoro- phenyl) -3,5-dihydroxy-8- [1- (1-methylethyl) -1H-tetrazol-5-yl] - 6,8-nonadienoate (230 mg, 0.45 mmol) in 10 ml of tetrahydrofuran 450µl (1.0 equivalent) of 1N NaOH solution added at 0 ° C (ice water bath). The emulsion was stirred at 0 ° C for 1 h, giving a homogeneous solution formed. Analytical TLC, 2 × with 50% EtOAc in hexane eluted, showed only one fixed point at the start. Most of the volatile solvent has been removed at reduced pressure and 10-15 ° C and the remaining aqueous solution lyophilized in a high vacuum at 0 ° C. The title compound was obtained in quantitative yield; Mp <120 ° C (decomposition).

IR (KBr) _Max :
3438 (v.br), 1600 (s), 1581 (s), 1513 (s), 1400 (s), 1225 (s), 1160 (s), 838 (s) cm^-1;

1 H NMR (DMSO-d₆) δ :
7.41-7.29 (4H, m), 7.07-6.91 (4H, m), 6.53 (1H, d, J = 15.6 Hz), 5.06 (1H, dd, J = 5.4, 15.7 Hz), 4.48 (1H, heptette, J = 6.6 Hz), 4.14 (1H, q, J = 5.9 Hz), 3.64 (1H, m), 3.8-3.2 (2H br. peaks), 2.02 (1H, dd, J = 3.6, 15 Hz), 1.84 (1H, dd, J = 8.4, 14 , 9 Hz), 1.5-1.3 (1H, m) 1.3-1.1 (1H, m) 1.15 (6H, br.s, isopropyl signals showed restricted rotation);

13 C NMR (DMSO-d₆) δ :
176.30, 161.82 (d, 1 J _CF = 246.1 Hz), 161.41 (d, 1 J _CF = 246.9 Hz), 151.53, 144.45, 139.87, 136.11 135 , 45, 132.14, (d, ³J _CF = 8.3 Hz), 131.28 (d, ³J _CF = 8.3 Hz), 125.39, 122.23, 115.44 (d, ²J _CF. = 21.9 Hz), 115.05 (d, ²J _CF = 21.9 Hz), 68.14, 65.68, 50.05 44.48, 43.48, 22.06 ppm;

Elemental analysis for C₂₅H₂₅F₂N₄O₄Na 2H₂O:

calculated: C 55.35%; H 5.39%; N 10.32% found: C 54.63%; H 4.79%; N 9.35%

Example 29 Sodium (±) erythro-11,11-bis (4-fluorophenyl) -3,5-dihydroxy- 10- [1- (1-methylethyl) -1H-tetrazol-5-yl] -6,8,10-undecatrienoate

The product from Example 26 was according to the general Implemented regulation of Example 28, the The title compound was obtained in quantitative yield; Mp = <100 ° C (decomposition).

IR (KBr) _Max :
3425 (v.br), 1600 (s), 1575 (sh, s), 1513 (s), 1400 (s), 1225 (s), 1163 (s), 838 (s) cm^-1;

1 H NMR (DMSO-d₆) δ :
7.42-7.30 (4H, m), 7.14-7.03 (2H, m), 6.92-6.87 (2H, m), 6.46 (1H, d, J = 15 , 4 Hz), 6.17 (1H, dd, J = 14.8, 15.4 Hz), 5.72 (1H, dd, J = 5.2, 14.9 Hz), 5.61 (1H , dd, J = 10.9, 15.3 Hz), 5 (1H, br), 4.48 (1H, heptett, J = 6.6 Hz), 4.12 (1H, m) 3.64 ( 1H, br), 2.01 (1H, d, J = 12.6 Hz), 1.84 (1H, dd, J = 8, 14.3 Hz), 1.6-0.8 (6H, v peak, isopropyl signals showed restricted rotation);

13 C NMR (DMSO-d₆) δ :
175.93, 162 (d, 1 J _CF = 250 Hz), 161 (d, 1 J _CF = 250 Hz), 151.35, 144.71, 141.56, 136.09, 135.57, 133.82, 132.31 (d, ³J _CF = 8.3 Hz), 131.41 (d, ³J _CF = 8.3 Hz), 128.65, 127.61, 122.58, 115.46 (d, ²J _CF. = 21.1 Hz), 115.14 (d, ²J _CF = 21.9 Hz), 68.41, 65.83, 50.11, 44.65, 43.51, 22.07 (v br. For Isopropyl carbon) ppm:

Example 30 Sodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- [2- (1-methylethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate

The ethyl 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [2- (1- methylethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate from Example 27 was made according to the general rule of example 28 implemented, the title compound in quantitative yield emerged. Mp <120 ° C (decomposition).

IR (KBr) _Max :
3438 (v. Br), 1600 (s), 1513 (s), 1483 (m), 1400 (m), 1321 (s), 1225 (s), 1188 (m), 1156 (s), 838 (s) cm^-1;

1 H NMR (DMSO-d₆) δ :
7.29-7.22 (4H, m), 6.95 (2H, t, J = 8.8 Hz), 6.84-6.78 (2H, m), 6.53 (1H, d, J = 15.6 Hz), 5.34 (1H, dd, J = 5.6, 15.6 Hz), 5.02 (1H, heptette, J = 6.7 Hz), 4.15 (1H, q, J = 5.9 Hz), 3.65 (1H, q, J = 4 Hz), 3.37 (2H, br.S, D₂O interchangeable), 2.04 (1H, dd, J = 15, 3.5 Hz), 1.85 (1H, dd, J = 8.6, 15.1 Hz), 1.40 (6H, d, J = 6.7 Hz), 1.47-1.23 ( 2H, br. Peaks);

13 C NMR (DMSO-d₆) δ :
176.28, 162.88, 161.59 (d, ¹J _CF = 246.13 Hz), 160.94 (d, ¹J _CF = 245.4 Hz), 143.20, 139.49, 137.81, 136.26, 132.06 (d, ³J _CF = 8.3 Hz), 131.30 (d, ³J _CF = 8.3 Hz), 130.93, 126.00, 125.85, 115.32 ( d, ²J _CF = 21.9 Hz), 114.46 (d, ²J _CF = 21.9 Hz), 79.09, 68.53, 65.83, 55.72, 44.64, 43.53, 30.36, 21.69 ppm.

Elemental analysis for C₂₅H₂₅F₂N₄O₄Na 2H₂O:

calculated: C 55.35%; H 5.39%; N 10.32% found: C 55.96%; H 4.86%; N 10.27%

Example 31 Sodium (±) erythro-7,7-bis (4-fluorophenyl) -3,5-dihydroxy-6- [2- (1-methylethyl) -2H-tetrazol-5-yl] -6-heptenoate

The ethyl 7,7-bis (4-fluorophenyl) -3,5-dihydroxy-6- [2- (1- methylethyl) -2H-tetrazol-5-yl] -6-heptenoate from Example 27 was carried out in accordance with the general test instructions of Example 28 implemented, the title compound in quantitative yield was obtained. Mp <120 ° C (decomposition)

IR (KBr) _Max :
3438 (s, v.br) 1600 (s), 1575 (s), 1512 (s), 1406 (s), 1225 (s), 1156 (s), 838 (s) cm^-1;

1 H NMR (DMSO-d₆) δ :
7.41-7.36 (2H, m), 7.23 (2H, t, J = 8.7 Hz), 6.93 (2H, t, J = 8.8 Hz), 6.86-6 , 82 (2H, m), 4.98 (1H, heptette, J = 6.7 Hz), 4.67 (1H, t, J = 6.7 Hz), 3.76 (1H, m), 3 , 35 (br.S, D₂O interchangeable), 1.99 (1H, dd, J = 3.15 Hz), 1.8-1.63 (3H, m), 1.41 (3H, d, J = 6.4 Hz), 1.38 (3H, d, J = 6.5 Hz);

13 C NMR (DMSO-d₆) w :
176.42, 161.34 (d, 1 J _CF = 244.6 Hz), 160.7 (d, 1 J _CF = 237.1 Hz), 162.25, 143.93, 137.88, 136.44, 131.11 (d, ³J _CF = 8 Hz), 130.85 (d, ³J _CF = 8 Hz), 114.97 (d, ²J _CF = 21.1 Hz), 114.33 (d, ²J _CF = 21.1 Hz), 67.76, 65.80, 55.40, 43.12, 42.89, 30.33, 21.78, 21.58 ppm (non-equivalent isopropyl signals).

Elemental analysis for C₂₃H₂₃F₂N₄O₄Na H₂O:

calculated: C 55.42%; H 5.05%; N 11.24% found: C 56.01%; H 4.94%; N 10.79%

Example 32 Ethyl-3,3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylethyl) -2H- tetrazol-5-yl] -2-propenoate

To a stirred suspension of 10 g of ethyl 3,3-bis (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate in 250 ml were cooled to -50 ° C and dried diethyl ether slowly 60 ml liquid isobutylene (in a dry ice Alcohol bath condensed from gaseous material) added. With continued stirring and cooling, 50 ml concentrated and slowly added sulfuric acid. The mixture was then placed in a stainless steel Parr vessel closed and stirred at -30 ° C for 40 h. After releasing the resulting excess pressure, the mixture became slowly and carefully an excess saturated NaHCO₃ solution added. The aqueous mixture became extracted with diethyl ether, dried over Na₂SO₄ and concentrated in a vacuum. From the title compound were 7.8 g (67.8%) exploited, mp 143-144 ° C.

IR (KBr) _Max :
3438 (v.br), 1738 (s), 1625 (s), 1600 (s), 1240 (s), 1225 (s), 842 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.29-7.24 (2H, m), 7.07-6.84 (6H, m), 4.10 (2H, q), 1.59 (9H, s), 1.03 (3H, t) ppm.

Elemental analysis for C₂₁H₂₂F₄N₄O₂:

calculated: C 64.07%; H 5.38%; N 13.58% found: C 64.15%; H 5.25%; N 13.58%

Example 33 3,3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylethyl) -2H-tetrazole- 5yl] -2-propenal A. 3,3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylethyl) -2H- tetrazol-5-yl] -2-propenol

To a stirred solution of ethyl 3,3-bis (4-fluorophenyl) - 2- [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -2-propenoate (2 g, 4.8 mmol) in dried methylene chloride (10 ml), 10 ml of diisobutylaluminum hydride solution (1.0 molar solution in methylene chloride) were added under argon at -78 ° C. in the course of 3 minutes. The reduction was carried out at -78 ° C under argon for 2 hours. Analytical TLC, eluted twice with 20% (v / v) ethyl acetate in hexane, showed no starting material at R _f = 0.42, but a major point at R _f = 0.14 for the desired product. The unpurified reaction mixture (at -78 ° C) was diluted with 10 ml of 2N HCl and then extracted with ethyl acetate (40 ml x 2). The organic phases were combined, dried over magnesium sulfate, evaporated under reduced pressure and dried under high vacuum at room temperature overnight. The title compound obtained was used for the next synthesis without a further purification step.

1 H NMR (60 MHz) (CDCl₃) δ :
7.4-6.9 (8H, m), 9.7 (≃1 / 4H, s, small amount of aldehyde), 4.6 (2H, d, J = 6 Hz), 1.56 (9H, s ) ppm.

B. 3,3-bis (4-fluorophenyl) -2- [2- (1,1-dimethylethyl) -2H-tetrazole- 5-yl] -2-propenal

The unpurified allyl alcohol from Step A was dissolved in 60 ml of dried methylene chloride. With vigorous stirring, pyridinium chlorochromate (1.2 g, 5.5 mmol) was added in one portion to the solution at room temperature and under argon. The slightly exothermic oxidation was carried out for 2 hours. Analytical TLC, 2 × with 20% (v / v) ethyl acetate in hexane, showed the aldehyde at R _f = 0.35. The unpurified reaction mixture was chromatographed on a silica gel column and eluted with 1 liter of 5% (v / v) ethyl acetate in hexane. 1.59 g (89%) of a product homogeneous according to TLC were exploited. Recrystallization from EtOAc-hexane gave the pure title compound; Mp 131-133 ° C.

IR (KBr) _Max :
3488 (m), 1669 (s), 1600 (s), 1508 (s), 1475 (m), 1231 (s), 1219 (s), 1156 (s), 850 (s) cm^-1;

1 H NMR (CDCl₃) δ :
9.72 (1H, s), 7.38-7.33 (2H, m), 7.17 (2H, t, J = 8.6 Hz), 7.00-6.84 (4H, m) 1.63 (9H, s);

13 C NMR (DMSO-d₆) δ :
190.14, 164.27 (d, 1 J _CF = 246.1 Hz), 163.35 (d, 1 J _CF = 240 Hz), 162.5, 160.9, 135.82, 133.58, (d , ³J _CF = 8.3 Hz), 132.26 (d, ³J _CF = 8.3 Hz), 128.4, 115.85 (d, ²J _CF = 21.9 Hz), 115.22 (d, 2 J _CF = 21.9 Hz), 63.95, 29.24 ppm;

Elemental analysis for C₂₀H₁₈F₂N₄O:

calculated: C 65.21%; H 4.92%; N 15.21% found: C 65.33%; H 4.93%; N 15.44%

Example 34 5,5-bis (4-fluorophenyl) -4- [2- (1,1-dimethylethyl) -2H-tetrazole- 5-yl] -2,4-pentadienal

To a warm, stirred solution of 3,3-bis (4-fluorophenyl) - 2- [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -2-propenal (1.59 g, 4 , 3 mmol) in 60 ml of dried benzene, triphenylphosphoranylidene acetaldehyde (1.45 g, 4.7 mmol) was added in one portion under argon. The reagents quickly dissolved in the warm (55 ° C) mixture. The homogeneous mixture was slowly warmed and refluxed for 16 h. Analytical TLC, eluted 5 × with 20% (v / v) ethyl acetate in hexane, showed the desired product at R _f = 0.52. The unpurified reaction mixture was chromatographed on a silica gel column and eluted with 10% (v / v) ethyl acetate in hexane. 1.7 g of the title product which was pure after recrystallization from EtOAc-hexane were obtained; Mp 171-174 ° C

IR (KBr) _Max :
3000 (s), 1675 (s), 1669 (s), 1600 (s), 1508 (s), 1225 (s), 1159 (s), 1119 (s), 843 (s) cm^-1;

1 H NMR (CDCl₃) δ :
9.55 (1H, d, J = 7.4 Hz), 7.50 (1H, d, J = 15.6 Hz), 7.33-7.26 (2H, m), 7.18-7 , 13 (2H, m), 6.92-6.79 (4H, m), 5.96 (1H, dd, J = 7.5, 15.6 Hz), 1.63 (9H, s);

13 C NMR (CDCl 3) δ :
193.38, 163.5 (d, ¹J _CF = 240 Hz), 162.5 (d, ¹J _CF = 240 Hz), 154.5, 151.5, 149.49, 137.0, 135.5, 132.81 (d, ³J _CF = 8.3 Hz), 132.05 (d, ³J _CF = 8 Hz), 115.8 (d, ²J _CF = 21.9 Hz), 114.98 (d, ²J _CF = 21.9 Hz), 64.3, 29.23 ppm;

Elemental analysis for C₂₂H₂₀F₂N₄O:

calculated: C 66.99%; H 5.10%; N 14.18% found: C 67.14%; H 5.17%; N 14.55%

Example 35 Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate A. Ethyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (1,1-di methylethyl) -2H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate

A solution of the dianion of ethyl acetate (400 ul, 3.1 mmol) in 8 ml of dried tetrahydrofuran was prepared according to the procedure of Example 10 using 130 mg (3.2 mmol) NaH (60% in mineral oil) and 2.5 M n-BuLi in hexane (1.27 ml, 3.2 mmol) at 0 ° C and under argon. The orange colored solution of the dianion, after cooling to -78 ° C., was cannulated into a tetrahydrofuran solution (12 ml) of 5,5-bis (4-fluorophenyl) -4- [2- (1,1-dimethylethyl ) -2H-tetrazol-5-yl] -2,4-pentadienal (0.96 g, 2.4 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 5 min. Analytical TLC, eluted 1x with 50% (v / v) EtOAc in hexane, showed the major product at R _f = 0.35. The reaction mixture was diluted with 20 ml of 1N HCl and the organic material extracted with EtOAc (20 ml × 2). The organic layers were combined, dried over MgSO₄, evaporated at reduced pressure and dried in a high vacuum (0.001 mmHg) at room temperature overnight (16 h). The title compound obtained was used in the next step without further purification.

B. Ethyl- (±) -erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- [2- (1,1-dimethylethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate

The unpurified ketone from Step A was dissolved in 10 ml of dried tetrahydrofuran under argon at 0 ° C. 3 ml of a 1 molar solution of triethylborane in tetrahydrofuran were added to this pale brown solution. The mixture was stirred at 0 ° C for 1.5 h and then cooled to -78 ° C (dry ice / acetone bath). 120 mg (3.2 mmol) of NaBH₄ were added to this stirred solution and the reduction was carried out at -78 ° C. for 3 h. The cold reaction mixture was diluted with 10 ml 1N HCl and the product extracted with ethyl acetate (40 × 2). The organic phases were combined, dried over MgSO₄ and evaporated to dryness. The crude product was redissolved in 200 ml of absolute methanol and the solution thus obtained was stirred for 16 hours. Analytical TLC, eluted 1 × with 50% (v / v) ethyl acetate in hexane, showed in main product at R _f = 0.31. After silica gel column chromatography with 10-20% EtOAc in hexane as eluent, the title compound was obtained in a yield of 83.5% (1.07 g).

IR (KBr) _Max :
3438 (s), 2988 (s), 1731 (s), 1600 (s), 1503 (v.s.), 1225 (s), 1156 (s), 838 (s), 750 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.28-7.24 (2H, m), 7.07 (2H, t, J = 8.6 Hz), 6.86-6.73 (4H, m), 6.69 (1H, d, J = 15.7 Hz), 5.48 (1H, dd, J = 6.3, 15.8 Hz), 4.44 (1H, m) 4.23 (1H, m), 4.16 (2H , q, J = 7 Hz), 3.85 (1H, br, D₂O interchangeable), 3.5 (1H, br. D₂O interchangeable), 2.48-2.45 (2H, m), 1.69- 1.54 (2H, m), 1.59 (9H, s), 1.26 (3H, t, J = 7 Hz);

13 C NMR (CDCl 3) δ :
172.38, 162.5 (d, 1 J _CF = 249.2 Hz), 161.82 (d, 1 J _CF = 248.4 Hz), 145, 53, 137.96, 136.96, 136.29, 132.35 (d, 3 J _CF = 8.3 Hz), 131.61 (d, 3 J _CF = 7.6 Hz), 128.39, 125.58, 115.31 (d, 2 J _CF = 21.9 Hz), 114.59 (d, ²J _CF = 21.9 Hz), 72.24, 68.10, 63.75, 60.75, 42.52, 41.62, 29.16, 14.15 ppm .

Elemental analysis for C₂₈H₃₂F₂N₄O₄H₂O:

calculated: C 61.75%; H 6.29%; N 10.28% found: C 61.22%; H 6.03%; N 10.02%

Example 36 Sodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- [2- (1,1-dimethylethyl-2H-tetrazol-5-yl] -6,8-nonadienecarboxylic acid, Sodium salt

To a solution of ethyl (±) -erythro-9,9-bis (4-fluor phenyl) -3,5-dihydroxy-8- [2- (1,1-dimethylethyl) -2H-tetrazole- 5-yl] -6,8-nonadienoate (330 mg, 0.63 mmol) in 6 ml of tetrahydrofuran 630 µl of a 1 molar NaOH Solution added. The cloudy solution was at 30 min 0 ° C and then stirred for 2.5 h at ambient temperature, forming a homogeneous solution. Analytical TLC Eluted 1x with 50% (v / v) ethyl acetate in hexane, showed except no starting product at the point at the start.

Most of the volatile solvent was added to evaporated under reduced pressure and a temperature of 10-15 ° C. The sodium salt solution of the product was in a high vacuum lyophilized, taking 320 mg (100%) of the title compound were obtained. Mp <120 ° C (decomposition).

IR (KBr) _Max :
3413 (v.br), 1600 (s), 1575 (s), 1503 (s), 13 99999 00070 552 001000280000000200012000285919988800040 0002003805801 00004 9988038 (s), 1225 (s), 1156 (s), 838 (s) cm^-1;

1 H NMR (DMSO-d₆) w :
7.29 (4H, d, J = 7.2 Hz), 6.95 (2H, t, J = 8.9 Hz), 6.83-6.78 (2H, m), 6.53 (1H, d, J = 15.5 Hz), 5.37 (1H, dd , J = 5.6, 15.6 Hz), 5.0 (1H, br. D₂O interchangeable), 4.16 (1H, q, J = 6.1 Hz), 3.67 (1H, m), 3.37 (1H, br. D₂O interchangeable, 2.05 (1H , dd, J = 15.1, 3.5 Hz), 1.86 (1H, dd, J = 8.6, 15.1 Hz), 1.53-1.29 (2H, m), 1.54 (9H, s);

13 C NMR (DMSO-d₆) δ :
176.40, 162.50, 161.54 (d, ¹J _CF = 246.1 Hz), 160.98 (d, ¹J _CF = 259.7 Hz), 143.15, 139.54, 137.87, 136.23, 132.0 (d, ³J _CF = 8.3 Hz), 131.25 (s, ³J _CF = 7.6 Hz), 125.91, 115.31 (d, ²J _CF = 21.9 Hz), 114.43 (d, ²J _CF = 21.9 Hz), 68.45, 65.75, 63.35, 44.64, 43.52, 28.53 ppm.

Elemental analysis for C₂₆H₂₇F₂N₄O₄ H₂O:

calculated: C 56.11%; H 5.61%; N 10.07% found: C 56.96%; H 5.06%; N 9.99%

Example 37 4,4'-difluoro-3,3'-dimethylphenone

2-fluorotoluene (8 ml, 73 mmol) was turned into a vigorous stirred mixture of aluminum chloride (61.43 g, 460 mmol) and carbon tetrachloride (135 ml) added at 0 ° C. After 10 min, 2-fluorotoluene (92 ml, 837 mmol) in carbon tetrachloride (75 ml) dropwise over a period of time added from 4 h and the mixture at 0 ° C another 2 h touched. Warning: A spontaneous violent reaction continued Add 2-fluorotoluene. The mixture was brought to -20 ° C cooled and quenched with 2N HCl (250 ml). The organic Phases were separated, washed with a saline solution and dried (MgSO₄). The solvent was evaporated off the residue dissolved in 200 ml of benzene and with water (200 ml) and treated with acetic acid (50 ml). After stirring for 15 hours the organic phase was separated off over magnesium sulfate dried and evaporated. Crystallization from ethanol gave 50 g (49%) of the title compound. Mp = 128-130 ° C.

IR (KBr) _Max :
1650 cm^-1.

1 H NMR (CDCl₃) δ :
7.66 (d, J = 7.3 Hz, 2H), 7.58 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 2.32 (s, 6H).

Elemental analysis for C₁₅H₁₂F₂O:

calculated: C 73.16%; H 4.91% found: C 72.96%; H 4.80%

Example 38 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol-

A solution of 1,5-dimethyltetrazole (2.55 g; 26 mmol) in dry tetrahydrofuran (15 ml) was at -78 ° C with n-butyllithium (12.5 ml of a 2.5 molar solution in hexane, 31.2 mmol) were added and the mixture was stirred for 15 min.

4,4'-difluoro-3,3'-dimethylbenzophenone (5 g, 20.3 mmol) in Dry tetrahydrofuran (20 ml) was added, the mixture Stirred for 1 h and then quenched with 2N HCl (250 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml) and the combined organic phases dried over MgSO₄ and evaporated. The residue was over silica gel column chromatography using 20% (v / v) EtOAc-hexane purified as eluent, taking 3.7 g (52%) of the product were obtained. Recrystallization from EtOAc-hexane gave the Title compound: mp 41-42 ° C.

IR (KBr) _Max :
3400 (br) cm^-1;

1 H NMR (CDCl₃) δ :
7.20 (d, J = 7.1 Hz), 2M), 7.10 (m, 2H), 6.88 (t, J = 8.6 Hz, 2H), 4.84 (s, 1H), 3.77 (s, 3H), 3.71 (s, 2H), 2.20 (s, 6H);

Elemental analysis for C₁₈H₁₈F₂N₄O:

calculated: C 62.79%; H 5.27%; N 16.27% found: C 62.73%; H 5.32%; N 16.16%

Example 39 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene

A mixture of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl- 1H-tetrazol-5-yl) ethanol (3.58 g; 10.9 mmol) and potassium hydrogen sulfate (530 mg) was heated at 195 ° C for 1.5 hours. After cooling the mixture to 70 ° C, 50 ml of chloroform added. Insoluble matter was removed by filtration removed and the filtrate evaporated. The residue was crystallized from EtOAc-hexane, 3.38 g (100%) of the Title compound were obtained. Mp 138-139 ° C.

1 H NMR (CDCl₃) δ :
7.20-6.80 (m, 6H), 6.65 (s, 1H), 3.56 (s, 3H), 2.28 (s, 3H), 2.18 (s, 3H).

Elemental analysis for C₁₈H₁₆F₂N₄:

calculated: C 66.25%; H 4.95%; N 17.17% found: C 66.15%; H 5.05%; N 17.24%

Example 40 3,3-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-prop-enal

A solution of 1,1-bis (4-fluoro-3-methylphenyl) -2- (1-methyl tetrazol-5-yl) ethene (3.58 g; 11.0 mmol) in dry tetrahydrofuran (20 ml) was added n-butyllithium (5.3 ml of a 2.5 molar solution in hexane; 13.25 mmol) was added at -78 ° C and the mixture was stirred at -78 ° C for 0.5 h. Ethyl format (1.33 ml; 1.22 g, 16.5 mmol) was added, the mixture warmed to 23 ° C over 1 h and then quenched with 2N HCl (250 ml). The aqueous phase was extracted with ethyl acetate (3 × 50 ml), the organic phases were dried (MgSO₄) and evaporated. The residue was purified by chromatography using 20% EtOAc-hexane as the eluent. 2.2 g (57%) of the title compound were obtained in a foamy form. MS (CI): m / e = 355 for (M + H) ⁺;

IR (KBr) _Max :
1660 cm^-1;

1 H NMR (CDCl₃) δ :
9.62 (s, 1H), 7.25-7.05 (m, 3H), 6.85-6.65 (m, 3H), 3.73 (s, 3H), 2.34 (s, 3H), 2.13 (s, 3H).

Elemental analysis for C₁₉H₁₆F₂N₄O:

calculated: C 64.41%; H 4.56%; N 15.82% found: C 64.60%; H 4.70%; N 15.62%

Example 41 5,5-bis (4-fluoro-3-methylphenyl) -4- (1-methyl-1H-tetrazole- 5-yl) -2,4-pentadienal

To a mixture of 3,3-bis (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (2.12 g, 5.98 mmol) and Triphenylphosphoranylidene acetaldehyde (1.89 g, 6.22 mmol) was added to dry benzene (26 ml) under an argon atmosphere. The suspension was quickly warmed to reflux in an oil bath under argon. The solid components dissolved very quickly at the reflux temperature and a dark brown color developed. The reaction was continued at the reflux temperature for 60 minutes. Analytical TLC, eluted 10 × with 20% (v / v) ethyl acetate in hexane, showed the desired product at R _f = 0.35. The unpurified reaction mixture was applied to a short silica gel bed and eluted with 2 l of 20% (v / v) ethyl acetate in hexane, whereby 2.12 g (93.3%) of the title compound (homogeneous according to TLC) were obtained. MS (CI): m / e = 381 for (M + H) ⁺

IR (KBr) _Max :
1679 (s), 1606 (s), 1591 (s), 1500 (s), 1438 (m), 1250 (s), 1231 (s), 1138 (s), 1125 (s) cm^-1;

1 H NMR (CDCl₃) δ :
9.53 (1H, d, J = 7.47 Hz), 7.44 (1H, d, J = 16.0 Hz), 7.15-7.09 (3H, m), 6.9-6.7 (3H, m), 5.80 (1H, dd, J = 15.6, 7.44 Hz), 3.55 (3H, s), 2.33 (3H, d, J = 1.9 Hz), 2.11 (3H, d, J = 1.8 Hz);

13 C NMR (CDCl 3) δ :
192.51, 162.4 (d, ¹J _CF = 250.7 Hz) 162.0 (d, ¹J _CF = 250 Hz), 156.23, 152.57, 147.82, 134.88, 134.83, 134.37, 133.77 (d, ³J _CF = 6.04 Hz), 133.19, (d , ³J _CF = 6.04 Hz), 131.94, 130.04 (d, ³J _CF = 8.31 Hz), 129.32 (d, ³J _CF = 8.31 Hz), 126.22, 126.00, 119.57, 115.66 (d, ²J _CF = 23.4 Hz), 115.59 (d, ²J _CF = 23.41 Hz), 33.64, 14.59, 14.36 ppm;

Elemental analysis for C₂₁H₁₈F₂N₄O:

calculated: C 66.31%; H 4.77%; N 14.73% found: C 66.36%; H 4.71%; N 14.15%

Example 42 Ethyl 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1- methyl 1H-tetrazol-5-yl) -3-oxo-6,8-nondienoate

A solution of the dianion of ethyl acetate acetate (1.42 ml, 11.1 mmol) in dry tetrahydrofuran (15 ml) was prepared according to the procedure of Example 10 using 450 mg (11.3 mmol) NaH (60% in mineral oil) and 4.5 ml (11.1 mmol) 2.5M n-BuLi in hexane at 0 ° C and under argon. After cooling to -78 ° C., the orange solution of the dianion was cannulated into a tetrahydrofuran solution (15 ml) containing 5.5-bis (4-fluoro-3-methylphenyl) -4- (1-methyl- 1H-tetrazol-5-yl) -2,4-pentadienal (2.12 g, 5.6 mmol) at -78 ° C. The reaction mixture was stirred at -78 ° C for 15 min. Analytical TLC, eluted 1 × with 50% (v / v) ethyl acetate in hexane, showed the main product at R _f = 0.16. The reaction mixture was diluted with 20 ml 1N HCl and the organic residue extracted with ethyl acetate (30 ml × 2). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure, whereby a whitish syrupy residue was obtained. The crude product was chromatographed on a silica gel column and eluted with 35% (v / v) ethyl acetate in hexane to give 1.39 g (48.7%) of the title compound. MS (CI): m / e = 511 for (M + H) ⁺;

IR (KBr) _Max :
3219 (v.s, br), 3000 (s), 1744 (s), 1719 (s), 1500 (s), 1325 (m), 1250 (s), 1231 (s), 1119 (s), 1035, (s), 735 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.1-7.0 (3H, m), 6.8-6.6 (3H, m), 6.68 (1H, d, J = 15.63 Hz), 5.30 (1H, dd, J = 5.76, 15.63 Hz), 4.63 (1H, br) , 4.18 (2H, q, J = 6.96 Hz), 3.54 (3H, s), 3.44 (2H, s), 2.93 (1H, br, D₂O interchangeable), 2.65-2.75 (2H, m), 2.29 (3H, d, J = 1.65 Hz), 2.08 (3H, d, J = 1.41 Hz), 1.27 (3H, t, J = 6.96 Hz);

13 C NMR (CDCl 3) δ :
166.66, 161.52 (d, ¹J _CF = 248.40 Hz), 161.13 (d, ¹J _CF = 250.66 Hz), 153.53, 148.08, 135.64, 135.26, 135.03, 133.44 (d, ³J _CF = 4.53 Hz), 132.71 (d, ³J _CF = 4.53 Hz), 129.58 (d, ³J _CF = 8.31 Hz), 128.73 (d, ³J _CF = 7.55 Hz), 128.36, 125.33, 125.44, 120.47, 115.21 (d, ²J _CF = 21.90 Hz), 67.93, 61.59 , 49.86, 49.07, 33.56, 14.46 (d, ³J _CF = 11.33 Hz), 14.33, 14.09 ppm;

Elemental analysis for C₂₇H₂₈F₂N₄O₄ H₂O:

calculated: C 61.36%; H 5.72%; N 10.60% found: C 62.47%; H 5.59%; N 8.23%

Example 43 Ethyl- (±) -erythro-9,9-bis (4-fluoro-3-methylphenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

The ethyl 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8- prepared in Example 42 nonadienoate (1.39 g, 2.7 mmol) was dissolved in 30 ml of tetrahydrofuran under argon at 0 ° C (ice water bath). To this yellow solution, 3 ml (3.0 mmol) of a triethylborane solution in tetrahydrofuran (1M in tetrahydrofuran) was added in one portion. The solution was stirred at 0 ° C for 1 h before it was cooled to -78 ° C (dry ice / acetone bath). Dry NaBH₄ (0.12 g, 3.2 mmol) was added to this stirred pale yellow solution and the reaction was carried out at -78 ° C. for a further h. The unpurified reaction mixture was diluted at -78 ° C. with 20 ml of 1N HCl and then warmed to room temperature. The organic components were extracted with ethyl acetate (30 ml x 2), the organic phases were combined, dried over magnesium sulfate and concentrated under reduced pressure to give a syrupy residue. The raw material was taken up again in 250 ml of methanol and the solution was left to stand at room temperature for 16 hours. Analytical TLC of the methanolic solution (eluted twice with 50% (v / v) ethyl acetate in hexane) showed the product at R _f = 0.1. The product was purified by silica gel column chromatography (elution with 20% (v / v) ethyl acetate in hexane). 0.95 g (68%) of the title compound were exploited from the correspondingly combined fractions. MS (CI): m / e = 513 for (M + H) ⁺.

IR (KBr) _Max :
3438 (s), 3000 (s), 1735 (s), 1500 (s), 1441 (s), 1250 (s), 1230 (s), 1119 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.08-7.02 (3H, m), 6.77 (1H, t, J = 8.91 Hz), 6.69-6.63 (2H, m), 6.66 (1H, d, J = 15.7 Hz), 5.31 (1H, dd, J = 6.12, 15.7 Hz), 4.42 (1H, br), 4.22 (1H, br), 4.16 (2H, q, J = 7.2 Hz), 3.80 (1H, br. D₂O interchangeable), 3.72 (1H, br. D₂O interchangeable ), 3.56 (3H, s), 2.45 (2H, d, J = 6.12 Hz), 2.28 (3H, d, J = 1.65 Hz), 2.08 (3H, d, J = 1.5 Hz), 1.8-1.57 (2H , m), 1.26 (3H, t, J = 7.2 Hz);

13 C NMR (CDCl 3) δ :
172.47, 161.1 (d, ¹J _CF = 248.4 Hz), 153.66, 147.5, 137.66, 137.31.135.78, 133.36, 132.68 (d, ³J _CF = 6.04 Hz), 129.58 (d, ³J _CF = 8.31 Hz), 128.68 (d , ³J _CF = 8.31 Hz), 127.43, 125.50, 115.16 (d, ²J _CF = 22.65 Hz), 71.98, 68.40, 60.88, 42.37, 41.45, 33.56, 14.53, 14.33, 14.15 ppm;

Elemental analysis for C₂₇H₃₀F₂N₄O₄:

calculated: C 63.27%; H 5.90%; N 10.93% found: C 62.80%; H 6.17%; N 10.34%

Example 44 Sodium (±) erythro-9,9-bis (4-fluoro-3-methylphenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate.

To a solution of ethyl (±) erythro-9,9-bis (4-fluoro-3-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6 , 8-nonadienoate (0.80 g; 1.56 mmol) in tetrahydrofuran (20 ml), a normal NaOH solution (1.56 ml) was added in one portion at 0 ° C. and under argon. The pale yellow emulsion was stirred at 0 ° C (ice water bath) for 2 hours to form a pale transparent solution. Analytical TLC, eluted with 20% (v / v) methanol in CHCl₃ showed the product at R _f = 0.16. Most of the organic volatile solvents were evaporated off under reduced pressure and the desired product was lyophilized under high vacuum. The title compound (0.8 g, 100%) contained approximately 1 mole of water.

IR (KBr) _Max :
3425 (v. Br), 1575 (s), 1500 (s), 1438 (s), 1400 (s), 1225 (s), 1116 (s) cm^-1;

1 H NMR (DMSO-d₆) δ :
7.26-7.19 (3H, m), 6.95 (1H, t, J = 8.91 Hz), 6.78-6.70 (2H, m), 6.49 (1H, d, J = 15.5 Hz), 5.13 (1H, dd, J = 5.43, 15.5 Hz), 4.15 (1H, br. Q, J = 6.03 Hz), 3.68 (3H, s), 3.67 (1H, br), 3.45 (2H, v. Br, D₂O interchangeable), 2.26 (3H, br. s), 2.05 (3H, br. s), 2.05 (1H, br), 1.85 (1H, dd, J = 8.37, 14 Hz), 1.55-1.25 (2H, m);

13 C NMR (DMSO-d₆) δ :
175.09, 159.03 (d, ¹J _CF = 242.36 Hz), 160.08 (d, ¹J _CF = 242.36 Hz), 151.84, 144.17, 138.35, 135.01 (d, ³J _CF = 3.78 Hz), 134.12 (d, ³J _CF = 3.02 Hz ), 131.83 (d, ³J _CF = 4.53 Hz), 130.83 (d, ³J _CF = 3.78 Hz), 128.34 (d, ³J _CF = 8.31 Hz), 127.11 (d, ³J _CF = 8.31 Hz), 123.84, 123.52, 123.30, 123.10, 112.87, 120.49, 113.99 (d, ²J _CF = 22.65 Hz), 113.69 (d, ²J _CF = 23.41 Hz), 67.66, 65.12, 44.12, 43.24, 33.18, 14.0, 14.15 ppm;

Elemental analysis for C₂₅H₂₅F₂N₄O₄Na 2H₂O:

calculated: C 55.35%; H 5.39%; N 10.33% found: C 55.01%; H 5.01%; N 9.82%

Example 45 Ethyl-3,3-bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) - 2-propenoate and ethyl 3,3-bis- (4-fluorophenyl) -2- (2-ethyl- 2H-tetrazol-5-yl) -2-propenoate A. Ethyl-3,3-bis- (4-fluorophenyl) -2- (2-ethyl-2H-tetrazole- 5-yl) -2-propenoate

To a solution of 10.0 g (0.028 mol) of ethyl 3,3-bis- (4- fluorophenyl) -2- (1H-tetrazol-5-yl) -2-propenoate (made in Example 2) in 75 ml of N, N-dimethylformamide were 1.2 g of 60% sodium hydride (0.03 mol) added in mineral oil. After stirring for 0.5 h, the sodium hydride was dissolved and then 8.5 g (0.056 mol) of iodoethane was added. The solution was stirred at room temperature for 16 h diluted with 400 ml of water and extracted with CH₂Cl₂. The Extracts were dried and concentrated in vacuo. The Residue was triturated with hexane to remove mineral oil. The residue was dissolved in CH₂Cl₂, in dry State of added silica gel adsorbed and then in vacuo concentrated to a dry powder. This material was applied to a silica gel column and with 10% (v / v) ethyl acetate eluted in hexane. There were 4.9 g (45.5%) of the title compound obtained; Mp = 113-114.5 ° C.

IR (KBr) _Max :
1710 (s), 1601 (s), 1505 (s), 1160 (s), 596 (s), 550 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.31-7.28 (m, 2H), 7.11-6.85 (m, 6H), 4.56 (q, 2H), 4.10 (q, 2H), 1.51 (t, 3H), 1.02 (t, 3H) ppm;

13 C NMR (CDCl 3) δ :
167.03, 165.62 (d), 165.28 (d), 162.64, 160.64 (d), 160.34 (d), 152.76, 136.86 (d), 136.00 (d), 131.92 (d), 131.75 (d), 131.10 (d) , 130.92 (d), 115.53 (d), 115.35 (d), 115.13 (d), 114.96 (d), 61.41, 48.31, 14.51, 13.70 ppm;

Analysis for C₂₀H₁₈F₂N₄O₂:

calculated: C 62.50%; H 4.73%; N 14.58% found: C 62.28%; H 4.72%; N 14.51%

B. Ethyl-3,3-bis- (4-fluorophenyl) -2- (1-ethyl-2H-tetrazole- 5-yl) -2-propenoate

Corresponding fractions after another elution the silica gel column from step A with 10% (v / v) ethyl acetate evaporated in hexane contained 5.1 g (47.4%) of Title link; Mp = 97-99 ° C.

IR (KBr) _Max :
1720 (s), 1605 (s), 1507 (s), 1160 (s), 845 (s), 540 (s) cm^-1;

1 H NMR (CDCl₃) δ :
7.40-6.90 (m, 8H), 4.00 (q, 2H), 3.88 (q, 2H), 1.16 (t, 3H), 1.00 (t, 3H) ppm;

Analysis for C₂₀H₁₈F₂N₄O₂:

calculated: C 62.50%; H 4.73%; N 14.58% found: C 62.27%; H 4.73%; N 14.51%

Example 46 3,3-bis (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenol

To a solution of ethyl 3,3-bis- (4-fluorophenyl) -2- (1- ethyl 1H-tetrazol-5-yl) -2-propenoate (1.0 g, 2.6 mmol) in Ch₂Cl₂ were at -78 ° C 7.8 ml (7.8 mmol) of a diiso butyl aluminum hydride solution (1.0 molar in methylene chloride) added quickly. After stirring for 45 minutes, the Quenched solution with 1N HCl. The organic phase was separated, dried (MgSO₄) and concentrated in vacuo. The oil obtained was triturated with hexane, 0.9 g (100%) of the title compound were obtained; Mp = 103-111 ° C.

1 H NMR (CDCl₃) δ :
7.41-7.34 (m, 2H), 7.18-7.09 (m, 2H), 6.91-6.87 (m, 4H), 4.7 (s, 2H), 3.80 (q, 2H), 1.21 (t, 3H) ppm;

13 C NMR (CDCl 3) δ :
166.04, 165.91 (d), 165.47 (d), 161.08, 160.84, 156.02, 135.78 (d), 134.22 (d), 131.73 (d), 131.69 (d), 131.55 (d), 131.51 (d), 116.01 ( d), 115.94 (d), 115.57 (d), 115.50 (d), 61.91, 42.85, 14.13 ppm;

Analysis for C₁₈H₁₆F₂N₄O:

calculated: C 63.16%; H 4.72%; N 16.37% found: C 62.99%; H 4.73%; N 16.40%

Example 47 3,3-bis (4-fluorophenyl) -2- (2-ethyl-1H-tetrazol-5-yl) -2-propenol

The general experimental procedure of Example 46 was repeated, the ethyl 3,3-bis- (4- fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2-propenoate by 1.0 g of ethyl 3,3-bis- (4-fluorophenyl) -2- (2-ethyl-2H- tetrazol-5-yl) -2-propenoate was replaced. From the title link 0.9 g were obtained; Mp = 82-84 ° C.

1 H NMR (CDCl₃) δ :
7.30-7.33 (m, 2H), 7.08-6.87 (m, 6H), 4.57 (d, 2H), 4.48 (d, 2H), 2.88 (t, 1H), 1.43 (t, 1H);

13 C NMR (CDCl 3) δ :
165.04, 164.82 (d), 164.67 (d), 160.12, 159.78, 147.08, 137.56 (d), 136.45 (d), 131.47 (d), 131.43 (d), 131.34 (d), 131.25 (d), 115.53 ( t), 115.13 (t), 114.72 (d), 62.89, 48.24, 14.40 ppm;

Analysis for C₁₈H₁₆F₂N₄O:

calculated: C 63.16%; H 4.72%; N 16.37% found: C 63.22%; H 4.74%; N 16.41%

Example 48 3,3-bis- (4-fluorophenyl) -2- (1-ethyl-1H-tetrazol-5-yl) -2- propenal

Pyridinium chlorochromate (0.9 g) became a solution of 0.8 g (2.3 mmol) 3,3-bis- (4-fluorophenyl) -2- (1-ethyl-1H- tetrazol-5-yl) -2-propenol in methylene chloride was added. The solution first turned yellow and then darkened below Formation of a dark, viscous precipitate. After 16 hours The mixture was stirred directly at room temperature applied a silica gel column and with methylene chloride eluted. 0.65 g (83%) of the title compound were obtained; Mp = 144-145 ° C.

IR (KBr) ν _max :
1680 (s), 1600 (s), 1515 (s), 1135 (s), 855 (s), 840 (s);

1 H NMR (CDCl₃) δ :
9.65 (1H, s), 7.36-7.20 (4H, m), 7.05-6.88 (4H, m), 4.01 (2H, q), 1.38 (3H, t);

13 C NMR (CDCl 3) δ :
189.02, 167.07 (d), 166.51 (d), 164.68, 162.04, 150.41, 133.65 (d), 133.49 (d), 132.34 (d), 132.18 (d), 124.11, 116.46 (d), 116.34 (d), 116.02 (d), 115.90 (d), 43.00, 14.24 ppm;

Analysis for C₁₈H₁₄F₂N₄O:

calc .: 63.53%; H 4.15%; N 16.47% Found: C 62.90%; H 4.13%; N 16.37%

Example 49 3,3-bis (4-fluorophenyl) -2- (2-ethyl-1H-tetrazol-5-yl) -2-propenal

The reaction of 4.0 g (12.0 mmol) of 3,3-bis (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-propenol with pyridinium chlorochromate (4.5 g) was according to the test instructions of Example 48, 3.25 g (79.7%) the title compound was obtained; Mp = 138-139 ° C.

1 H NMR (CDCl₃) δ :
9.70 (1H, s), 7.39-7.32 (2H, m), 7.23-7.14 (2H, m), 7.04-6.86 (4H, m), 4.62 (2H, q), 1.56 (3H, t);

13 C NMR (CDCl 3) δ :
190.04, 166.71 (d), 165.86 (d), 163.01, 161.68, 161.16 (d), 160.86 (d), 135.62 (d), 135.55 (d), 133.69 (d), 133.53 (d), 132.37 (d) , 137.19 (d), 127.74, 116.06 (t), 115.59 (t), 115.17 (t), 48.45, 14.59 ppm;

Analysis for C₁₈H₁₄F₂N₄O:

calc .: 63.53%; H 4.15%; N 16.47% Found: C 63.53%; H 4.11%; N 16.74%

Example 50 5,5-bis- (4-fluorophenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -2,4- pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- (1-ethyl-1H- tetrazol-5-yl) -2-propenal (0.65 g, 1.9 mmol) and 0.64 g 2.1 mmol) triphenylphosphoranylidene acetaldehyde in benzene were heated at reflux temperature for 2 hours. The solution was concentrated in vacuo and the residue obtained by silica gel column chromatography with CH₂Cl₂ as Eluent cleaned. From the title compound were 0.55 g (79.7%) obtained; Mp = 163-165 ° C.

1 H NMR (CDCl₃) δ :
9.54 (1H, d), 7.49 (1H, d), 7.42-6.96 (8H, m), 5.76 (1H, dd), 8.89 (2H, q), 1.27 (3H, t);

13 C NMR (CDCl 3) δ :
192.41, 166.21 (d), 165.77 (d), 161.18, 160.71, 155.04, 151.58, 150.10, 148.34, 148.27, 147.91, 138.90, 134.97, 134.53, 132.77, 132.60, 132.20, 132.03, 120.35, 116.43, 116.26, 116.03, 115.78, 42.66, 14.30 ppm;

Analysis for C₂₀H₁₆F₂N₄O:

calc .: 65.57%; H 4.41%; N 15.30% Found: C 65.32%; H 4.77%; N 14.76%

Example 51 5,5-bis- (4-fluorophenyl) -4- (2-ethyl-1H-tetrazol-5-yl) -2,4- pentadienal

The experimental protocol of Example 50 was used 3.25 g (9.5 mmol) of 3,3-bis- (4-fluorophenyl) -2- (2-ethyl-2H-tetrazol-5-yl) -2-propenal and 3.05 g (10.0 mmol) Triphenylphosphoranylidene acetaldehyde repeated, where 3.3 g (95%) of the title compound were formed; Mp = 117-120 ° C.

1 H NMR (CDCl₃) δ :
9.45 (1H, d), 7.49 (1H, d), 7.34-7.11 (4H, m), 7.00-6.78 (4H, m), 5.94 (1H, dd), 4.60 (2H, q), 1.52 (3H, t);

13 C NMR (CDCl 3) δ :
193.23, 165.83, 165.08, 162.91, 160.83, 160.10, 154.47, 151.28, 149.46, 140.21, 132.89, 132.72, 132.13, 132.00, 130.56, 116.00, 115.56, 115.28, 114.89, 48.46, 14.63 ppm;

Analysis for C₂₀H₁₀F₂N₄O:

calc .: 65.57%; H 4.41%; N 15.30% Found: C 65.36%; H 4.40%; N 15.64%

Example 52 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-ethyl-1H- tetrazol-5-yl) -3-oxo-6,8-nonadienoate

To a solution of 0.5 g (1.4 mmol) of 5,5-bis- (4-fluorophenyl) -4- (1-ethyl-1H-tetrazol-5-yl) -2,4-pentadienal in tetrahydrofuran 1.75 ml of 0.8 M (1.4 mmol) of a freshly prepared solution of the ethyl acetate dianion (described in Example 10) are added at -50 ° C. The solution was stirred at -50 ° C for 30 minutes and warmed to -10 ° C over the next 30 minutes. The solution was quenched with 1N HCl and extracted with methylene chloride. The organic extracts were dried and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent chloroform). 0.4 g of the oily title compound were obtained.
MS (CI): m / e = 497 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.29-7.11 (4H, m), 6.87-6.83 (4H, m), 6.72 (1H, d), 5.24 (1H, dd), 4.62 (1H, m), 4.16 (2H, q), 3.88 (2H, q), 3.44 (2H, s), 3.30 (1H, d), 2.71 (2H, d), 1.25 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
166.69, 165.31, 164.92, 160.32, 159.95, 152.64, 146.82, 136.7, 135.98, 135.34, 135.26, 135.18, 132.38, 132.20, 131.62, 131.45, 128.26, 121.25, 115.92, 115.78, 115.48, 115.34, 91.48, 67.75, 61.51, 49.87, 49.14, 42.55, 14.27, 14.09 ppm.

Example 53 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (2-ethyl-2H- tetrazol-5-yl) -3-oxo-6,8-nonadienoate

To a solution of 5,5-bis- (4-fluorophenyl) -4- (2-ethyl-2H-tetrazol-5-yl) -2,4-pentadienal (2.0 g) in 20 ml of tetrahydrofuran were added 6. 9 ml of a 0.8 M (5.5 mmol) freshly prepared solution of the ethyl acetate dianion (described in Example 10) were added at -40 ° C. The solution was stirred at -40 ° C for 30 minutes and then warmed to -10 ° C. After a total of 1 h, the reaction was quenched with 1N HCl. The mixture was extracted with chloroform, dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain 0.4 g of the pure title compound.
MS (EI): m / e = 496 for M⁺.

¹H MNR (CDCl₃) δ :
7.29-7.22 (2H, m), 7.13-7.04 (2H, m), 6.90-6.78 (4H, m), 6.71 (1H, d), 4.68-4.48 (3H, m), 4.15 (2H, q ), 3.45 (2H, s), 2.73 (3H, d with broad shoulder), 1.49 (3H, t), 1.27 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
164.95, 164.28, 163.91, 159.99, 159.39, 145.98, 137.64, 137.56, 136.20, 136.06, 135.21, 132.42, 132.25, 131.71, 131.53, 128.90, 115.54, 115.10, 114.93, 114.48, 91.31, 68.11, 61.44, 49.93, 49.36, 48.28, 14.62, 14.10 ppm;

In addition, 1.55 g of unpurified title compound were obtained, which were used without further cleaning.

Example 54 Ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) -6,8-nonadienoate

To a solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-ethyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate (0, 5 g; 1.0 mmol) in tetrahydrofuran, 1.1 ml (1.1 mmol) of a triethylborane solution (1.0 molar solution in tetrahydrofuran) were added at 0.degree. The solution was stirred for 2.5 h and then cooled to -78 ° C. Sodium borohydride (0.08 g; 2.0 mmol) was added, followed by 0.5 ml of methanol. After stirring for 2.5 h at -78 ° C, the mixture was diluted with an equal volume of hexane and quenched with 1N HCl, followed by extraction with ethyl acetate. The organic extracts were dried (MgSO₄), concentrated in vacuo, dissolved in methanol and then stirred at room temperature for 16 h. The solution was concentrated in vacuo and the product was purified by silica gel column chromatography with an eluent of 2% methanol in chloroform. 0.3 g of the oily title compound were obtained.
MS (EI): m / e = 498 for M⁺.

1 H NMR (CDCl₃) δ :
7.27-7.13 (4H, m), 6.88-6.84 (4H, m), 6.71 (1H, d), 5.28 (1H, dd), 4.18 (1H, m), 4.17 (3H, q over broad m), 3.88 (2H, q), 3.71 (2H, dd), 2.45 (2H, d), 1.59 (3H, t), 1.28 (3H, t), ppm.

13 C NMR (CDCl 3) δ :
172.37, 165.26, 164.87, 160.31, 159.90, 146.38, 137.77, 135.89, 135.82, 135.28, 132.29, 132.17, 131.61, 131.43, 127.39, 121.48, 115.89, 115.75, 115.49, 115.30, 71.80, 60.86, 42.48, 42.25, 41.47 14.26, 14.18 ppm.

Example 55 Ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -6,8-nonadienoate and Ethyl- (±) -erythro-7,7-bis- (4-fluorophenyl) -3,5-dihydroxy- 6- (2-ethyl-2H-tetrazol-5-yl) 6-heptenoate A. Ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -6,8-nonadienoate

To a solution of 1.55 g (3.0 mmol) of unpurified ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (2-ethyl-2H-tetrazol-5-yl) -3 -oxo-6,8-nonadienoate (prepared in Example 53) in tetrahydrofuran, 3.3 ml (3.3 mmol) of a 1M triethylborane solution (1.0M solution in tetrahydrofuran) were added at 0 ° C. After stirring for 2.5 h, the solution was cooled to -78 ° C and 0.25 g (6.3 mmol) sodium borohydride, followed by 1.2 ml methanol was added. After stirring for a further 2.5 h, the reaction mixture was diluted with an equal volume of hexane and quenched with 1N HCl. The mixture was extracted with ethyl acetate, the combined organic phases were dried (MgSO₄) and concentrated in vacuo. The residue was taken up in methanol and stirred at room temperature for 16 hours. The methanolic solution was concentrated in vacuo and the residue was purified by silica gel column chromatography with an eluent of 1% CH₃OH in CHCl₃. The appropriate fractions were combined and evaporated under reduced pressure to give 0.65 g of the title compound in an oily form.
MS (EI): m / e = 498 for M⁺.

1 H NMR (CDCl₃) δ :
7.30-7.02 (4H, m), 6.80-6.72 (4H, m), 6.68 (1H, d), 5.45 (4H, dd), 4.52 (2H, q), 4.48 (1H, m), 4.15 (3H, q over m), 3.72 (1H, m), 2.45 (2H, dd), 1.67 (2H, m), 1.45 (3H, t), 1.25 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
164.92, 164.29, 164.11, 163.99, 159.98, 159.34, 145.65, 141.24, 137.69, 134.64, 136.83, 136.29, 136.21, 132.39, 132.23, 131.69, 131.51, 128.40, 125.09, 115.53, 115.10, 114.93, 114.51, 72.17, 68.09, 60.78, 48.26, 42.50, 41.66, 14.68, 14.19 ppm.

B. Ethyl- (±) -erythro-7,7-bis- (4-fluorophenyl) -3,5-dihydroxy- 6- (2-ethyl-2H-tetrazol-5-yl) 6-heptenoate

The appropriate fractions of the column eluate from Step A were combined and evaporated to give 0.2 g of the title compound; Mp = 124-128 ° C.
MS (EI): m / e = 473 for MH⁺.

1 H NMR (CDCl₃) δ :
7.32-6.78 (8H, m), 4.93 (1H, m), 4.55 (2H, q), 4.17 (3H, q over m), 3.88 (1H, d), 3.64 (1H, d), 2.45 (2H, dd), 1.83 (2H, m), 1.46 (3H, t), 1.27 (3H, t) ppm);

13 C NMR (CDCl 3) δ :
177.18, 164.94, 164.44, 163.16, 160.01, 159.51, 146.58, 137.11, 137.05, 135.92, 135.86, 131.31, 131.15, 130.98, 127.98, 115.73, 115.31, 115.01, 114.58, 71.44, 68.56, 67.86, 65.28, 60.72, 48.33, 42.44, 41.74, 41.44, 41.36, 14.53, 14.21 ppm;

Analysis for C₂₄H₂₆F₂N₄O₄ 0.5 H₂O:

calc .: 59.87%; H 5.66%; N 11.64% Found: C 59.62%; H 5.62%; N 11.21%

Example 56 Sodium (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy- 8- (1-ethyl-1H-tetrazol-5-yl) -6,8-nonadienoate

A solution of 1.0 g (2.0 mmol) of ethyl 9,9-bis (4-fluorophenyl) 3,5-dihydroxy-8- (1-ethyl-1H-tetrazol-5-yl) -6 , 8-nonadienoate and 2 ml (2.0 mmol) of 1N sodium hydroxide in 25 ml of ethanol were stirred for 45 min. The reaction mixture was concentrated in vacuo and the residue was taken up in water. The aqueous solution was lyophilized in vacuo to give the title compound containing about 1 mole of water; Mp = 193-203 ° C.
MS (FAB): m / e = 493 for M + H) ⁺.

IR (KBr) ν _max :
3200 (v. Br.), 1650 (br), 1600 (s), 1580 (s), 1510 (s), 1410 (br), 1230 (s), 850 cm ^-1 ;

1 H NMR (CDCl₃) δ :
7.37-7.29 (4H, m), 7.05-6.88 (4H, m), 6.50 (1H, d), 5.08 (1H, dd), 4.12 (1H, m), 4.04 (2H, q), 3.62 (1H, m), 3.35 (2H), 2.03-1.78 (2H, m), 1.46-1.23 (2H, m), 1.18 (3H, t) ppm;

Analysis for C₂₄H₂₃F₂N₄O₄Na H₂O:

calc .: 56.48%; H 4.94%; N 10.98% Found: C 56.28%; H 4.96%; N 10.56%

Example 57 Sodium (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy- 8- (2-ethyl-2H-tetrazol-5-yl) -6,8-nonadienoate

A solution of 0.65 g (1.3 mmol) ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (2-ethyl-2H-tetrazole- 5-yl) - 6,8-nonadienoate and 1.3 ml (1.3 mmol) of a 1N sodium hydroxide solution in 25 ml of ethanol were stirred for 1 hour. The reaction solution was concentrated in vacuo and the residue taken up in water. The aqueous solution was lyophilized in vacuo to give the title compound; Mp = 170-190 ° C.
MS (FAB): m / e = 493 for (M + H) ⁺.

IR (KBr) n _max :
3200 (v. Br.), 1650 (br), 1605 (s), 1580 (s), 1512 (s), 1410 (br), 1230 (s), 850 (s) cm ^-1 ;

1 H NMR (DMSO-d₆) δ :
7.34-6.79 (8H, m), 6.50 (1H, d), 5.31 (1H, dd), 5.0 (1H, br.m), 4.58 (2H, q), 4.13 (1H, m), 3.63 (1H, m), 3.35 (1H, br.m), 2.03-1.78 (2H, m), 1.46-1.21 (2H, m), 1.34 (3H, t) ppm.

Analysis for C₂₄H₂₃F₂N₄O₄Na 1.3 H₂O:

calc .: 55.88%; H 5.00%; N 10.86% Found: C 55.41%; H 4.67%; N 10.54%

Example 58 Sodium (±) erythro-7,7-bis (4-fluorophenyl) -3,5-dihydroxy- 6- (2-ethyl-2H-tetrazol-5-yl) 6-heptenoate

A solution of 0.2 g (0.45 mmol) of ethyl (±) erythro-7.7- bis- (4-fluorophenyl) -3,5-dihydroxy-6- (2-ethyl-2H-tetrazole-5- yl) -6-heptenoate (prepared in Example 55, step B) and 0.45 ml (0.45 mmol) of a 1N sodium hydroxide solution in 10 ml of ethanol was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure and the residue taken up in methanol. The aqueous solution was in vacuo lyophilized to give the title compound.

1 H NMR (CDCl₃) δ :
7.3-6.7 (8H, m), 5.7 (2H, br.m), 4.8 (1H, m), 4.4 (2H, q), 3.9 (1H, m), 3.65 (1H, m), 2.7 (2H, m), 1.9 (2H, m), 1.2 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
179.64, 164.64, 164.26, 163.27, 163.59, 159.71, 159.35, 145.67, 137.52, 137.46, 136.06, 135.98, 131.34, 131.20, 129.12, 115.65, 115.22, 114.86, 114.44, 70.30, 58.30, 48.18, 18.41, 14.48 ppm;

Analysis for C₂₂H₂₁F₂N₄O₄Na 2H₂O:

calc .: 52.59%; H 5.02%; N 11.16% Found: C 52.81%; H 5.32%; N 9.64%

Example 59 1,1-bis- (2,4-dimethylphenyl-2- (1-methyl-1H-tetrazol-5-yl) - ethanol

A solution of 1,5-dimethyltetrazole (8.9 g; 91.0 mmol) in 100 ml of dried tetrahydrofuran was treated with n-butyllithium (48 ml of a 1.89 M solution; 91.0 mmol) at -60 ° C. After stirring for 20 minutes, 2,2 ', 4,4'-tetramethylbenzophenone (18 g; 76 mmol) (made after Methods described in "J. Am. Chem. Soc., 81, 4858 (1959)) in 50 ml of dried tetarhydrofuran and stirred the solution for 1 hour, during which time it allowed to warm to -20 ° C. The reaction was carried out with 1N HCl quenched and then extracted with chloroform. The United organic extracts were dried (MgSO₄) and evaporated. The yield was 22 g of the title compound; Mp = 175-177 ° C.

IR (KBr) ν _max :
3390 (br), 1620 (s), 1460 (s), 1200 (s), 820 (s) cm ^-1 ;

1 H NMR (CDCl₃) δ :
7.26 (2H, d), 6.95-6.83 (4H, m), 4.00 (1H, s), 3.82 (2H, s), 3.41 (3H, s), 2.23 (6H, s), 1.83 (6H, s) ppm;

13 C NMR (CDCl 3) δ :
152.34, 139.28, 137.32, 135.79, 133.24, 126.26, 125.92, 77.47, 35.04, 32.99, 21.28, 20.76 ppm;

Analysis for C₂₀H₂₄N₄O:

calc .: C 71.41%; H 7.20%; N 16.67% Found: C 70.82%; H 7.26%; N 16.45%

Example 60 1,1-bis- (2,4-dimethylphenyl-2- (1-methyl-1H-tetrazol-5-yl) - ethics

A mixture of 1,1-bis (2,4-dimethylphenyl) -2- (1-methyl- 1H-tetrazol-5-yl) ethanol (1.8 g; 5.4 mmol) and potassium hydrogen sulfate (100 mg) was preheated to 190 ° C Oil bath warmed up. After 15 min the melt became cooled and methylene chloride added to the residue. The insoluble matter was removed and the Evaporated solution. The residue was made from isopropyl ether recrystallized, 1.2 g of the title compound have been obtained; Mp = 143-143.5 ° C.

IR (KBr) ν _max :
2930 (s), 1635 (s), 1620 (s), 1510 (s), 1450 (s), 820 (s), 740 (s) cm ^-1 ;

1 H NMR (CDCl₃) δ :
7.15-6.80 (6H, m), 6.60 (1H, s), 3.40 (3H, s), 2.36 (3H, s), 2.30 (3H, s), 2.18 (3H, s), 1.85 (3H, s) ppm;

13 C NMR (CDCl 3) δ :
154.18, 152.21, 138.54, 138.38, 138.06, 135.67, 135.40, 135.18, 131.78, 131.72, 129.90, 129.66, 126.77, 126.55, 111.99, 33.65, 21.02, 20.69, 19.95 ppm;

Analysis for C₂₀H₂₂N₄:

calc .: 75.45%; H 6.97%; N 17.60% Found: C 75.04%; H 7.03%; N 17.63%

Example 61 3,3-bis- (2,4-dimethylphenyl-2- (1-methyl-1H-tetrazol-5-yl) - 2-propenal

A solution of 1,1-bis (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.0 g; 3.1 mmol) in 10 ml of dry tetrahydrofuran was reacted with n-butyllithium (1.64 ml of a 1.89 M solution; 3.1 mmol) at -78 ° C. After stirring for 30 minutes while cooling, ethyl format (0.3 g; 4.0 mmol) was added and the mixture was stirred for a further 2 hours while cooling. The reaction was quenched with 1N HCl and then extracted with chloroform. The combined organic fractions were dried (MgSO₄) and evaporated. The residue was purified by silica gel column chromatography (eluting with 10% (v / v ethyl acetate in hexane) to give 0.9 g of the oily product. Trituration of the oil with isopropyl ether gave the title compound as a solid, mp = 117-120 ° C.
MS (CI): m / e = 347 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
9.58 (1H, s), 7.25-6.78 (7H, m), 3.70 (3H, s), 2.40 (3H, s), 2.25 (3H, s), 2.20 (3H, s), 1.90 (3H, s) ppm;

13 C NMR (CDCl 3) δ :
189.49, 168.80, 151.05, 140.87, 140.26, 137.06, 135.86, 134.87, 133.28, 132.04, 129.60, 126.62, 125.28. 34.17, 21.21, 21.06, 20.37, 20.07 ppm;

Analysis for C₂₁H₂₂N₄O:

calc .: 72.81%; H 6.41%; N 16.18% Found: C 72.99%; H 6.43%; N 16.09%

Example 62 5,5-bis- (2,4-dimethylphenyl-4- (l-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal

A solution of 3,3-bis (2,4-dimethylphenyl-2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (4.5 g; 13.0 mmol) and triphenyl phosphoranylidene acetaldehyde (4.1 g; 13.0 mmol) in benzene was heated to reflux for 6 h, the reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel with 10% (v / v) ethyl acetate in hexane as eluent, 5.9 g of the title compound were obtained in an oily form.
MS (CI): m / e = 373 for (M + H) ⁺.

IR (KBr) ν _max :
1742 (s), 1680, 1615, 1450 (s), 1130 (s), 830 (s), 810 (s) cm ^-1 ;

1 H NMR (CDCl₃) δ :
9.42 (1H, d), 7.3 (1H, d), 7.14-6.85 (6H, m), 5.80 (1H, dd), 3.52 (3H, s), 2.35 (3H, s), 2.20 (6H, s) , 1.85 (3H, s) ppm;

13 C NMR (CDCl 3) δ :
192.53, 158.44, 152.18, 150.60, 148.18, 139.45, 139.25, 136.14, 135.98, 135.18, 134.63, 131.78, 131.70, 131.28, 130.10, 126.45, 126.25, 121.26, 33.61, 20.90, 20.71, 20.18, 20.11 ppm;

Analysis for C₂₃H₂₄N₄O:

calcd: C 74.17%; H 6.50%; N 15.05% Found: C 72.82%; H 6.85%; N 13.33%

Example 63 Ethyl 9,9-bis (2,4-dimethylphenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate

The general experimental procedure of Example 42 was repeated, with the 5,5-bis (4-fluoro- 3-methylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4- pentadienal was replaced by 5.9 g (16.0 mmol) 5.5- Bis- (2,4-dimethylphenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal and the raw material formed over Silica gel column chromatography with 1% (v / v) methanol in Methylene chloride was purified as the eluent, whereby 4 g of the title compound were obtained.

1 H NMR (CDCl₃) δ :
7.10-6.95 (3H, m), 6.83-6.75 (3H, m), 6.50 (1H, d), 5.30 (1H, dd), 4.60 (1H, m), 4.14 (2H, q), 3.60 (3H, s), 3.43 (2H, s), 3.0 (1H, bs), 2.70 (2H, d), 2.35 (3H, s), 2.20 (3H, s), 1.90 (3H, s), 1.28 (3H, tppm ;

13 C NMR (CDCl 3) δ :
202.15, 166.59, 153.39, 149.71, 138.17, 136.15, 135.98, 135.81, 135.32, 134.96, 131.63, 131.42, 130.34, 130.04, 128.22, 126.36, 126.21, 122.03, 67.91, 61.34, 49.79, 49.24, 33.76, 21.06, 20.89, 20.49, 20.28, 14.02 ppm;

Analysis for C₂₉H₃₄N₄O₄:

calc .: 69.31%; H 6.82%; N 11.15% Found: C 68.29%; H 6.91%; N 10.88%

Example 64 Ethyl- (±) -erythro-9,9-bis- (2,4-dimethylphenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

The general experimental procedure of Example 43 was repeated using the ethyl 9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) used herein. -3-oxo-6,8-nonadienoate was replaced by 4 g (8.0 mmol) of ethyl 9,9-bis (2,4-dimethylphenyl) -5-hydroxy-8- (1-methyl-1H- tetrazol-5-yl) -6,8-nonadienoate and the resulting raw material were purified by silica gel column chromatography with 1% (v / v) methanol in methylene chloride as the eluent, to give 2.5 g of the title compound.
MS (CI): m / e = 505 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.10-6.90 (3H, m), 6.85-6.68 (3H, m), 6.43 (1H, d), 5.30 (1H, dd), 4.40 (1H, m), 4.35-4.08 (3H, q over m), 3.90 (1H, s), 3.78 (1H, s), 3.58 (3H, s), 2.47 (2H, d), 2.30 (3H, s), 2.15 (6H, s), 1.88 (3H, s), 1.60 (2H, m), 1.25 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
172.23, 153.67, 149.39, 149.31, 138.18, 136.87, 136.14, 135.95, 135.52, 131.75, 131.54, 130.17, 127.62, 126.47, 126.32, 122.37, 72.05, 68.26, 60.76, 42.48, 41.70, 33.86, 21.18, 21.00, 20.64, 20.40, 14.21 ppm;

Analysis for C₂₉H₃₆N₄O₄:

calc .: 69.03%; H 7.20%; N 11.11% Found: C 68.13%; H 7.25%; N 10.84%

Example 65 Sodium (±) erythro-9,9-bis (2,4-dimethylphenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

A solution of ethyl (±) erythro-9,9-bis (2,4-dimethylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6.8 - Nonadienoate (2.5 g; 4.95 mmol) in ethanol was mixed with a sodium hydroxide solution (4.95 ml of a 1.0 N solution; 4.95 mmol). After stirring for 1.5 h, an analytical TLC, eluted with 25% (v / v ethyl acetate in hexane, showed no starting product. The solution was concentrated in vacuo and the desired product was lyophilized under high vacuum, whereby the title compound was obtained as a beige powder.
MS (FAB); m / e = 498 for M⁺.

IR (KBr) ν _max :
3200 (v.br), 1620 (shoulder), 1580 (br), 1450, 1410, 705 (s) cm ^-1 ;

1 H NMR (D₂O) δ :
6.93-6.41 (6H, m), 6.31 (1H, d), 5.21 (1H, dd), 4.23-4.17 (1H, m), 3.93 (1H, m), 3.66 (3H, s), 3.59 (2H, q), 2.31-2.10 (2H, m), 2.01 (3H, s), 1.73 (3H, s), 1.67 (3H, s), 1.65-1.48 (1.5H, m), 1.12 (= 2H, t) ppm;

Analysis for C₂₇H₃₁N₄O₄Na 0.7 mol EtOH:

calc .: 64.27%; H 6.69%; N 10.56% Found: C 64.48%; H 6.84%; N 10.56%

Example 66 Ethyl-3,3-bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) - methyl 1H-tetrazol-5-yl] -2-propenoate and ethyl 3,3-bis- (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H- tetrazol-5-yl] -2-propenoate

Sodium hydride (60%, 0.67 g in mineral oil, 14.0 mmol) became a solution of ethyl-3,3-bis- (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2 -propenoate (5.0 g; 14.0 mmol) (prepared in Example 2) in dimethylformamide (50 ml) was added and the mixture was stirred to form a clear solution. MEM chloride (2-methoxyethoxymethyl chloride) (3.5 g; 28.0 mmol) was then added and the mixture was stirred for 64 h. The mixture was diluted with water (200 ml) and extracted with methylene chloride. The organic extracts were dried (MgSO₄) and the solution concentrated in vacuo to give 6 g of the title compounds in an oily form and approximately in a 1: 1 ratio (determined by 1 H NMR).
MS (CI): m / e = 445 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.29-6.84 (8H, m), 5.84 (2H, s), 5.43 (2H, s), 4.06 (2H, m), 3.53-3.40 (4H, m), 3.37 (3H, s), 0.99 (3H, m) ppm;

13 C NMR (CDCl 3) δ :
166.23, 165.90, 165.78, 165.59, 165.12, 163.15, 162.34, 160.93, 160.77, 160.62, 160.20, 157.36, 153.61, 152.20, 136.66, 136.61, 135.94, 135.88, 134.53, 134.45, 132.20, 132.03, 131.88, 131.73, 131.19, 131.03, 130.87, 120.04, 115.85, 115.66, 115.49, 115.42, 115.22, 115.05, 114.96, 95.54, 92.21, 80.97, 76.79, 71.69, 71.10, 70.95, 69.53, 69.09, 67.37, 66.73, 61.70, 61.38, 58.89, 36.35, 31.30, 27.80, 26.76, 17.65, 13.60, 13.52 ppm;

Example 67 3,3-bis- (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H- tetrazol-5-yl] -2-propenol and 3,3-bis (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenol

A solution of diisobutylaluminum hydride (65 ml of a 1M solution; 65.0 mmol) in methylene chloride was converted into a solution of ethyl 3,3-bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) - methyl 1H-tetrazol-5-yl] -2-propenoate and ethyl 3,3-bis- (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenoate (6.0 g; 13.0 mmol) (prepared in Example 66) in methylene chloride (50 ml) was added at -78 ° C. After stirring at -78 ° C for 3 hours, the reaction was hydrolyzed by adding excess 1N HCl. The aqueous phase was separated and extracted with methylene chloride. The combined organic phases were dried and concentrated in vacuo to give 5.2 g of the title compounds in oily form and in an approximate 1: 1 ratio (determined by 1 H NMR).
MS (EI): m / e = 402 for M⁺.

Analysis for C₂₀H₂₀F₂N₄O₃:

calc .: 59.70%; H 5.02%; N 13.93% Found: C 59.89%; H 5.09%; N 13.99%

Example 68 3,3-bis- (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H- tetrazol-5-yl] -2-propenol and 3,3-bis (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenal

Pyridinium chloride (6.6 g) became a solution of 3,3-bis (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenol and 3,3-bis (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenol (5.2 g; 13.0 mmol) (prepared in Example 67) added in methylene chloride. After stirring for 18 h at room temperature, the reaction had darkened and a viscous precipitate had formed. The reaction mixture was decanted and the methylene chloride solution dried in vacuo. The residue was purified by silica gel column chromatography with methylene chloride as the eluent, whereby 3 g of the title compounds were obtained in an oily form and in an approximate 1: 1 ratio (determined by 1 H NMR).
Ms (EI): m / e = 400 for M⁺.

1 H NMR (CDCl₃) δ :
9.73 (1H, s), 9.60 (1H, s), 7.44-6.91 (9H, m), 5.92 (2H, s), 5.57 (2H, s), 3.68-3.38 (7H, m) ppm;

13 C NMR (CDCl 3) δ :
189.62, 188.78, 166.87, 166.57, 166.34, 165.68, 165.60, 163.17, 161.85, 161.65, 161.55, 161.29, 160.66, 151.11, 134.39, 134.33, 133.43, 133.55, 133.37, 133.08, 132.42, 132.25, 132.06, 129.34, 129.19, 128.96, 127.22, 123.65, 116.12, 115.94, 115.69, 115.50, 115.26, 115.07, 80.92, 77.01, 70.87, 69.40, 69.26, 68.83, 62.06, 58.78, 50.23, 46.41 ppm;

Example 69 3,3-bis- (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H- tetrazol-5-yl] -2-propenal and 5,5-bis- (4-fluorophenyl) -4- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2,4-pentadienal A. 3,3-bis- (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H- tetrazol-5-yl] -2-propenal

A solution of 3,3-bis- (4-fluorophenyl) -2- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenal and 3,3-bis- (4th -fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -2-propenal (3.5 g; 8.75 mmol) (prepared in Example 68) and triphenylphosphoranylidene acetaldehyde (1.33 g; 4.4 mmol) in benzene (50 ml) was heated to reflux for 6 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 15% (v / v ethyl acetate in hexane). Concentration of the appropriate fractions resulted in effective separation and isolation of the unreacted title compound.
MS (CI): m / e = 401 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
9.70 (1H, s), 7.40-6.80 (9H, m), 5.85 (2H, s), 3.60-3.40 (4H, m), 3.35 (3H, s) ppm;

13 C NMR (CDCl 3) δ :
189.66, 166.66, 165.76, 163.21, 161.72, 163.21, 161.72, 161.64, 160.75, 149.10, 135.46, 135.38, 133.61, 133.44, 133.27, 133.16, 132.79, 132.64, 132.31, 132.14, 131.94, 131.86, 127.32, 116.01, 115.91 115.56, 115.14, 80.99, 70.91, 69.46, 58.89 ppm;

B. 5,5-bis (4-fluorophenyl) -4- [1- (2-methoxyethoxy) methyl-1H- tetrazol-5-yl] -2,4-pentadienal

Further elution of the silica gel column from step A gave the desired product. The appropriate fractions were combined and evaporated under reduced pressure to give 1.1 g of the title compound.
MS (CI): m / e = 427 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
9.60 (1H, d), 7.45 (1H, d), 7.38-6.80 (8H, m), 5.70 (1H, dd), 5.30 (2H, s), 3.68-3.40 (4H, m) 3.30 (3H, s ) ppm;

13 C NMR (CDCl 3) δ :
192.42, 166.17, 165.72, 161.16, 160.70, 155.23, 152.49, 147.96, 135.04, 134.96, 134.55, 134.48, 132.90, 132.73, 132.21, 132.04, 131.85, 119.94, 116.31, 116.08, 115.87, 115.64, 76.67, 71.01, 69.53, 58.96 ppm.

Example 70 5,5-bis- (4-fluorophenyl) -4- [2- (2-methoxyethoxy) methyl- 2H-tetrazol-5-yl] -2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -2-propenal (1.4 g; 3.5 mmol) and triphenylphosphoranylidene acetaldehyde (1.3 g; 4.3 mmol) (isolated in Example 69, step A) in 25 ml of benzene was heated to reflux temperature for 12 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel with 20% (v / v) ethyl acetate in hexane as the eluent. 0.9 g of the title compound were obtained in an oily form.
MS (CI): m / e = 427 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
9.52 (1H, d), 7.48 (1H, d), 7.32-7.10 (4H, m), 6.92-6.75 (4H, m), 5.85 (3H, s over dd), 3.6-3.5 (4H, m), 3.35 (3H, s) ppm;

13 C NMR (CDCl 3) δ :
193.07, 165.85, 165.04, 163.50, 160.85, 160.07, 154.72, 149.12, 136.61, 136.59, 135.29, 135.24, 133.64, 133.47, 132.84, 132.67, 132.35, 132.13, 131.96, 131.91, 123.79, 115.99, 115.55, 115.35, 114.93, 81.12, 70.69, 69.55, 58.98 ppm.

Example 71 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (2-methoxy ethoxy) methyl 1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate

Ethylacetoacetate dianion (2.6 ml of a 1M solution freshly prepared according to the instructions of Example 10) became a solution of 5,5-bis (4-fluorophenyl) -4- [1- (2-methoxy ethoxy) methyl-1H -tetrazol-5-yl] -2,4-pentadienal (1.1 g; 2.6 mmol) in 15 ml tetrahydrofuran added at -40 ° C. After stirring for 2 hours, analytical TLC, eluted with 25% (v / v) ethyl acetate in hexane, showed starting aldehyde and therefore a further 1.2 ml of the dianion solution was added. The reaction mixture was warmed to 0 ° C and then quenched with 1N HCl. The mixture was extracted with methylene chloride, dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel column chromatography with 1% (v / v) methanol in methylene chloride as an eluent, whereby 0.9 g of the title compound was obtained in an oily form.
MS (CI): m / e = 557 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.5-6.6 (9H, m), 5.43 (2H, s), 5.00 (1H, dd), 4.6 (1H, m), 3.7-3.4 (6H, s over m), 3.30 (3H, s), 2.72 ( 2H, d), 1.22 (3H, t) ppm.

Example 72 Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (2-methoxy ethoxy) methyl 1H-tetrazol-5-yl] -3-oxo-6,8-nonadienoate

Ethyl acetate dianion (2.1 ml of a 1M solution freshly prepared according to Example 10) was added to a solution of 5,5-bis (4-fluorophenyl) 4- [2- (2-methoxyethoxy) methyl-2H-tetrazole-5- yl] -2,4-pentadienal (0.9 g; 2.0 mmol) in 15 ml of tetrahydrofuran at -50 ° C. After stirring for 1 hour, a further ml of the dianion solution was added and the mixture was stirred for a further 30 min. The reaction mixture was quenched with 1N HCl and then extracted with methylene chloride. The organic extracts were dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel column chromatography with 1% (v / v) methanol in methylene chloride as an eluent to obtain 0.55 g of the title compound.
MS (CI): m / e = 557 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.30-7.05 (4H, m), 6.90-6.70 (5H, m), 5.85 (2H, s), 5.35 (1H, dd), 4.70-4.53 (1H, m), 4.17 (2H, q), 3.48 ( 4H, m), 3.38 (3H, s), 2.72 (2H, d), 1.26 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
202.03, 190.30, 166.60, 164.88, 164.36, 164.15, 159.92, 146.22, 137.49, 137.41, 135.13, 132.29, 132.13, 131.63, 131.47, 131.18, 131.05, 131.02, 130.93, 128.67, 124.46, 115.45, 115.03, 114.92, 114.51, 91.16, 80.80, 70.84, 69.28, 67.96, 61.37, 58.90, 49.82, 49.18, 14.01 ppm.

Example 73 Ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) 3,5-dihydroxy-8- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -6.8- nonadienoat

To a solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -3-oxo-6, 8-nonadienoate (0.9 g; 1.6 mmol) in tetrahydrofuran (20 ml) was added at -10 ° C triethylborane (2.1 ml of a 1M solution) and the mixture was stirred for 45 min, the initially yellow solution became colorless. The solution was cooled to -78 ° C and sodium borohydride (0.13 g; 3.2 mmol) and methanol (0.75 ml) were added. After 2 h at -78 ° C the solution was diluted with 50 ml of hexane and hydrolyzed with 1N HCl. The aqueous phase was separated and extracted with ethyl acetate. The combined organic solutions were dried (MgSO₄) and concentrated in vacuo. The residue was dissolved in methanol (30 ml) and the resulting solution was stirred for 40 hours. The solution was concentrated in vacuo and the residue was purified by silica gel column chromatography eluting with 1% (v / v) methanol in methylene chloride to give 0.4 g of the title compound.
MS (CI): m / e = 559 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.4-6.8 (8H, m), 6.65 (1H, d), 5.40 (2H, s), 4.95 (1H, dd), 4.4-3.5 (8H, m), 3.30 (3H, s), 2.40 (2H, d), 1.80-1.35 (2H, m) 2.20 (3H, t) ppm.

Example 74 Ethyl- (±) -erythro-9,9-bis- (4-fluorophenyl) 3,5-dihydroxy-8- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -6.8- nonadienoat

To a solution of ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -3-oxo-6, 8-nonadienoate (0.9 g; 1.6 mmol) in tetrahydrofuran (15 ml) was added at -0 ° C triethylborane (2.1 ml of a 1M solution; 2.1 mmol) and the solution over a period of 1 , 5 h stirred, the yellow color disappearing. The mixture was cooled to -75 ° C and sodium borohydride (0.13 g; 3.2 mmol) and methanol (0.9 ml) were added. After stirring for 2 hours, the solution was diluted with 50 ml of hexane and hydrolyzed by adding 1N HCl. The aqueous phase was separated and extracted with ethyl acetate. The combined organic fractions were dried (MgSO₄) and concentrated in vacuo. The residue was diluted in methanol and the solution was stirred for 16 hours. The methanolic solution was concentrated in vacuo and the residue was purified by silica gel column chromatography with 1.5% (v / v) methanol in methanol chloride as the eluent to obtain 0.6 g of the title compound.
MS (CI): m / e = 559 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.38-7.04 (4H, m), 6.92-6.65 (5H, m), 6.92 (2H, s), 6.40 (1H, dd), 4.45 (1H, m), 4.15 (3H, q over m), 3.43 ( 4H, s), 3.32 (3H, s), 2.45 (2H, d), 1.72-1.65 (2H, m), 1.25 (3H, t) ppm;

13 C NMR (CDCl 3) δ :
172.45, 165.05, 164.69, 164.32, 160.12, 159.40, 146.06, 137.75, 137.70, 136.96, 136.13, 132.44, 132.28, 131.82, 131.66, 131.40, 131.25, 131.05, 128.32, 124.91, 115.65, 115.40, 115.23, 114.92, 114.69, 80.97, 72.25, 71.05, 69.48, 68.22, 60.90, 59.15, 42.53, 41.06, 14.27 ppm.

Example 75 Sodium (±) erythro-9,9-bis (4-fluorophenyl) 3,5-dihydroxy 8- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -6.8- nonadienoat

A solution of ethyl (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [1- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -6,8-nonadienoate (0.3 g; 0.54 mmol) and sodium hydroxide (0.54 ml of a 1N solution; 0.54 mmol) in ethanol (15 ml) were stirred for 3 h. The solution was concentrated in vacuo and the desired product was lyophilized under high vacuum to give 250 mg of the title compound containing about 2 moles of water; Mp = 110-135 ° C.
MS (FAB): m / e = 553 for (M + H) ⁺.

1 H NMR (D₂O) δ :
7.38-7.33 (2H, m), 7.22-7.18 (2H, t), 6.98-6.89 (4H, m), 6.67 (1H, d), 5.50 (2H, s), 5.23 (1H, dd), 4.27 ( 1H, m), 3.93 (1H, m), 3.61-3.46 (4H, m), 3.28 (3H, s), 2.30-2.28 (2H. M), 1.68-1.50 (2H, m) ppm;

13 C NMR (D₂O) δ :
181.37, 165.49, 165.02, 162.75, 162.27, 149.52, 138.74, 137.38, 136.57, 133.84, 133.75, 132.97, 132.88, 129.29, 121.34, 116.98, 116.73, 116.49, 78.19, 72.00, 71.02, 70.74, 68.31, 59.58, 46.05, 44.11 ppm;

Elemental analysis for C₂₆H₂₇F₂N₄O₆ Na 2H₂O:

calculated: C 53.06%; H 5.31%; N 9.53% found: C 53.36%; H 5.04%; N 9.02%

Example 76 Sodium (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy- 8- [2- (2-methoxyethoxy) methyl-2H-tetrazol-5-yl] -8.9- nonadienoat

A solution of ethyl (±) erythro-9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- [2- (2-methoxyethoxy) methyl-1H-tetrazol-5-yl] -6,8-nonadienoate (0.45 g; 0.81 mmol) and sodium hydroxide (0.81 ml of a 1N solution; 0.81 mmol) in ethanol (10 ml) was stirred for 30 min. The solution was concentrated in vacuo and the desired product was lyophilized under high vacuum to give 350 mg of the title compound as an orange powder; Mp = 175-190 ° C.
MS (FAB): m / e = 551 for (M + H) ⁺.

IR (KBr) ν _max :
3400 (v.br), 1603, 1585, 1515 (s), 1410 (br), 1230 842 (s) cm ^-1 ;

1 H NMR (D₂O) δ :
7.17-7.11 (2H, m), 7.02-6.97 (2H, t), 6.81-6.58 (5H, m), 5.86 (2H, s), 5.35 (1H, dd), 4.26 (1H, m), 3.97- 3.93 (1H, m), 3.41-3.24 (4H, m), 3.22 (3H, s), 2.33-2.21 (2H, m), 1.67-1.48 (2H, m) ppm;

Elemental analysis for C₂₆H₂₇F₂N₄O₆ Na O, 5H₂O:

calculated: C 55.62%; H 5.03%; N 9.98%; H₂O 1.60% found: C 55.46%; H 5.03%; N 9.79%; H₂O 1.89%

Example 77 5,5-bis- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal

To a mixture of 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (71.6 g; 0.22 mol) and tri phenylphosphoranylidene Acetaldehyde (66.8 g; 0.22 mol) was added 1.1 l of dry benzene and the suspension was heated to reflux for 30 min. The reaction was carried out at the reflux temperature for 2 hours. Analytical TLC, developed 5 times with 30% (v / v) ethyl acetate in hexane, showed a main point at R _f = 0.37, which corresponded to the desired product. The hot, crude reaction mixture was diluted with an equal volume of hexane and the warm mixture was quickly filtered through an activated carbon bed. The filtrate was left to stand at room temperature and 58.12 g (75.2%) of the desired product was isolated therefrom. A second crystallization of the filtrate gave predominantly triphenylphosphine oxide. Concentration of the filtrate gave an additional amount of the desired product, achieving the overall title compound yield of 71 g (91.8%). The combined material was recrystallized from ethyl acetate / hexane to give the pure title compound; Mp = 164-165 ° C. 1 H NMR from the recrystallized material showed no detectable double homologated product.

Elemental analysis for C₁₉H₁₄F₂N₄O:

calculated: C 64.77%; H 4.01%; N 15.90% found: C 65.20%; H 4.09%; N 16.03%

Example 78 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - propenal A. 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - ethanol

To a solution of 1,5-dimethyltetrazole (0.98 g; 10.0 mmol) in tetrahydrofuran (20 ml) became n-butyllithium at -30 ° C (4.7 ml of a 2.14M solution; 10.0 mmol) was added. To After stirring for 0.25 h, the solution was cooled to -50 ° C and 4,4'-difluorobenzophenone (1.74 g; 8.0 mmol) added. After stirring for 1 hour at -50 ° C and 1 hour Stirring at -10 ° C the reaction was with 1N HCl quenched. The mixture was extracted with methylene chloride, dried and evaporated in vacuo. The residue was by silica gel column chromatography with 40% (v / v) ethyl acetate purified in hexane as the eluent, whereby 2.0 g of the title compound were obtained; Mp = 116-118 ° C.

Elemental analysis for C₁₆H₁₄F₂N₄O:

calculated: C 60.76%; H 4.47%; N 17.72% found: C 60.62%; H 4.52%; N 17.63%

B. 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - ethics

A mixture of 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H- tetrazol-5-yl) ethanol (4.2 g; 12.7 mmol) (made in Step A) and potassium hydrogen sulfate was on for 0.5 h Heated at 195 ° C. After cooling, the mixture became Chloroform dissolved and washed with water. The organic Phase was dried and evaporated in vacuo. The The residue was triturated with diethyl ether, after which 3.9 g the title compound was obtained; Mp = 169-171 ° C.

Elemental analysis for C₁₆H₁₂F₂N₄:

calculated: C 64.43%; H 4.06%; N 18.88% found: C 63.93%; H 4.00%; N 19.25%

C. 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - propenal

To a finely divided suspension of 1,1-bis- (4-fluor phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethene (1.0 g; 3.3 mmol) (prepared in Step B) in tetrahydrofuran (10 ml) at -80 ° C n-butyllithium (1.54 ml of a 2.14M solution; 3.3 mmol) to form a dark purple color added. After stirring for 40 min at -80 ° C ethyl format (0.32 g; 4.3 mmol) was added and the Mixture stirred at -80 ° C for 2.5 h. The mixture became hydrolyzed with 1N hydrochloric acid and with methylene chloride extracted. The extracts were dried (MgSO₄) and evaporated in vacuo. The residue was washed with diethyl ether stirred, giving 0.77 g of a yellow solid were obtained, mp = 128-131 ° C. The solid became crystallized from isopropyl acetate / hexane, whereby 0.55 g of the title compound were obtained; Mp = 130-132 ° C.

Elemental analysis for C₁₇H₁₂F₂N₄O:

calculated: C 62.58%; H 3.71%; N 17.18% found: C 62.15%; H 3.82%; N 16.75%

Example 79 5,5-bis- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal

A solution of 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H- tetrazol-5-yl) propenal (1.0 g; 3.07 mmol) and triphenylphosphoranylidene acetaldehyde (0.93 g; 3.07 mmol) in benzene was heated to reflux temperature for 1 hour. The benzene was removed in vacuo and the reflux by silica gel column chromatography with 15% (v / v) ethyl acetate in hexane purified as eluent, using 0.7 g of the title compound have been obtained; Mp = 156-157.5 ° C.

Elemental analysis for C₁₉H₁₄F₂N₄O:

calculated: C 64.77%; H 4.01%; N 15.91% found: C 65.13%; H 4.05%; N 15.71%

Example 80 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenal A. 5-ethyl-1-methyl-1H-tetrazole

To 1,5-dimethyltetrazole (4.9 g; 0.05 mmol), slurried in dry tetrahydrofuran (50 ml), 2.5M n-butyllithium in hexane (20 ml; 0.05 mol) over a period of 15 min added at -78 ° C and under an inert atmosphere. This mixture was stirred for 30 minutes while stirring yellowish precipitate. Methyl iodide (3.7 ml; 0.06 mol) was then in a period of 15 min added. After stirring for a further 30 minutes the clear reaction mixture diluted with water and with Ethyl acetate (3 x 50 ml) extracted. The aqueous phase became washed with chloroform (2 x 25 ml), the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure, leaving an oily residue was incurred. The oil was purified by distillation whereby 5.2 g (92%) of the title compound were obtained; Bp = 89-90 ° C at 0.05 mm Hg.

1 H NMR (CDCl₃) δ :
4.05 (s, 3H), 2.86 (q, 2H), 1.41 (t, 3H).

13 C NMR (CDCl 3) δ :
156.0, 33.24, 16.75, 11.20.

B. 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - propanol

To a solution of 5-ethyl-1-methyl-1H-tetrazole (5.6 g; 0.05 mmol) (prepared in stage A) in 60 ml of dried Tetrahydrofuran were 2.5M n-butyllithium (20 ml; 0.05 mol) in hexane for 5 min at -78 ° C (bath temperature) added under an inert atmosphere. The mixture was stirred for 30 minutes and then in one Period of 5 minutes with a solution of 4,4'-difluorobenzophenone (10.8 g; 0.5 mol) in 25 ml of dried tetrahydrofuran transferred. This mixture was stirred for a further 2 h while the bath temperature was raised to -20 ° C. The reaction was quenched with 1N HCl and with ethyl acetate (3 x 50 ml) and chloroform (3 x 50 ml) extracted. The combined organic phases were over sodium sulfate dried and concentrated under reduced pressure, whereby a white solid remained. The solid became purified by crystallization from ethanol / hexane, whereby 10.8 g (65%) of the title compound were obtained; Mp = 160-161 ° C.

IR (KBr) ν _max :
3400 cm ^-1 ;

1 H NMR (CDCl₃) δ :
7.8-7.02 (m, 8H), 5.95 (s, 1H), 4.65 (q, 1H), 3.98 (s, 3H), 1.29 (d, 2H).

13 C NMR (CDCl 3) δ :
162.57, 162.37, 159.14, 156.71, 142.48, 140.54, 128.25, 128.13, 127.52, 127.42, 114.67, 114.41, 114.38, 78.56, 36.99, 33.43, 14.52.

Elemental analysis for C₁₇H₁₆F₂N₄O:

calculated: C 61.81%; H 4.88%; N 16.96% found: C 61.79%; H 4.90%; N 17.09%

C. 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 1-propen

A suspension of 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H- tetrazol-5-yl) propanol (8.25 g; 0.025 mol) (made in stage B) and 100 mg of p-toluenesulfonic acid monohydrate in Xylene (60 ml) was in a Dean & Stark water separator Heated to reflux temperature for 12 hours. The reaction mixture was warmed with 1N NaOH (10 ml) and with Washed water (100 ml). Concentration of organic Phase gave off white crystals as a product. This was purified by recrystallization from ethanol / hexane, 7.1 g (91%) of the title compound as white crystals have been obtained; Mp = 146-147 ° C.

IR (KBr) ν _max :
1575; 1500 cm ^-1 .

1 H NMR (CDCl₃) δ :
7.42-6.85 (m, 8H), 3.53 (s, 3H), 2.14 (s, 3H);

13 C NMR (CDCl 3) δ :
163.37, 163.08, 160.13, 155.61, 144.60, 145.34, 136.47, 136.42, 136.24, 136.19, 131.65, 131.54, 131.11, 131.01, 119.53, 115.51, 115.27, 115.22, 33.50, 21.20.

Elemental analysis for C₁₇H₁₄F₂N₄:

calculated: C 65.37%; H 4.51%; N 17.94% found: C 65.64%; H 4.61%; N 18.09%

D. 3,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazole- 5-yl) -2-propene

A suspension of 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H- tetrazol-5-yl) propene (61.46 g; 0.197 mol) (made in step C), N-bromosuccinimide (35.06 g; 0.197 mol) and a catalytic amount of azobis-isobutyronitrile or Benzoyl peroxide in carbon tetrachloride (1.2 L) was in an inert atmosphere at reflux temperature for 2 hours heated. The reaction mixture was brought to room temperature cooled and the solid components were removed from the Filtered reaction mixture. The filtrate was reduced Pressure concentrated and the solid obtained Crystallized residue from toluene / hexane, 72 g (93%) of the title compound as white crystals were; Mp = 159-160 ° C.

IR (KBr) n _max :
1600 cm ^-1 .

1 H NMR (CDCl₃) δ :
7.5-7.1 (m, 8H), 4.44 (s, 2H), 3.53 (s, 3H).

13 C NMR (CDCl 3) δ :
163.94, 163.74, 160.60, 160.45, 143.42, 149.68, 135.20, 135.15, 134.69, 131.43, 131.31, 130.90, 130.80, 119.57, 115.94, 115.77, 115.65, 115.50.

Elemental analysis for C₁₇H₁₃F₂BrN₄:

calculated: C 52.19%; H 3.34%; N 14.32% found: C 52.58%; H 3.47%; N 14.49%

E. 3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenal

To a solution of sodium ethoxide (3.93 g of sodium metal, 0.17 mol) in 500 ml of absolute ethanol 2-nitropropane (16.66 g; 0.187 mol) slowly within Added 5 min. The step D synthesized bromine compound (67.1 g; 0.17 mol) added in protests over a period of 10 min. The reaction mixture was stirred for 2 hours and then removed ethanol in vacuo. The residue was dissolved in CH₂Cl₂ (500 ml), with water (250 ml) washed and dried over sodium sulfate. The organic Phase was concentrated under reduced pressure, after which there was an oily residue. This oil was in hot Dissolved toluene (350 ml) and stirred with hexane (350 ml), where 50.6 g (91%) of the title compound as white crystals have been obtained; Mp = 135-137 ° C.

Example 81 1,1-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 1-propen-3-yl triphenylphosphonium bromide

A slurry of 3,3-bis (4-fluorophenyl) -1-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene (1.95 g, 0.005 mol) (prepared in Example 80, Step D) and triphenylphosphine (1.3 g, 0.005 mol) in cyclohexane (25 ml) becomes Heated to reflux. After 30 minutes the reaction mixture a clear solution and appears after 1 hour a white precipitate. The mixture is used for further Heated for 8 hours, cooled to room temperature and the solid is collected by filtration and washed with diethyl ether. You dry that white powder in vacuum at 50 ° C and receives 3.0 g (92%) the title compound; M.P. = 254-255 ° C.

IR (KBr) n _max :
3450, 1600, 1500, 1425 cm ^-1 .

1 H NMR (DMSO-d₆) δ :
7.92-6.80 (m, 23H), 4.94 (6d, 2H), 3.83 (s, 3H);

13 C NMR (DMSO-d₆) δ :
163.53, 163.36, 160.28, 160.87, 154.04, 153.89, 152.76, 135.11, 134.79, 134.16, 133.68, 133.54, 130.53, 130.45, 130.35, 130.21, 130.07, 118.02, 116.89, 116.18, 115.89, 115.62, 115.32, 111.43, 111.39, 34.22, 28.88, 28.22.

Elemental analysis for C₃₅H₂₈BrF₂N₄P:

calculated: C 64.31%; H 4.32%; N 8.57% found: C 64.02%; H 4.37%; N 8.89%

Example 82 Methyl (±) -erythro-9,9-bis (4-fluorophenyl) 3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

To a slurry of the phosphonium bromide (0.326 g, 0.5 mmol) (made in Example 81) and methyl erythro-3,5-bis (diphenyl-t-butylsilyloxy) -6-oxohexanoate (made according to the general procedures, described by P. Kapa et al. in Tetrahedron Letters, 2435-2438 (1984) and in U.S. Patent No. 45 71,428 issued Feb. 18, 1986 to PK Kapa) (0.26 g, 0.4 mmol ) in dry dimethylformamide (1 ml), potassium t-butoxide (0.067 g, 0.6 mmol) is added at -20 ° C. (bath temperature) in an inert atmosphere. The slurry is a red solution and stirred at -10 ° C for 18 hours. The reaction mixture is worked up by adding ammonium chloride solution (10 ml) and extracted with methylene chloride (2 × 30 ml). The organic layer is dried over sodium sulfate and concentrated to give an oil. The oil is purified through a bed of silica gel and the main fraction is isolated as an oil (160 mg). The oil (160 mg) is stirred with 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) and a few drops of glacial acetic acid for 18 hours. The reaction mixture is poured into water (10 ml) and extracted with ethyl acetate (3 × 20 ml). The organic layer is dried over sodium sulfate and concentrated to give an oil. The oil is purified by silica gel flash column chromatography and, eluted with ethyl acetate: hexane (2: 1), yields 0.08 g (75%) of the title compound as an oil. MS (CI) m / e = 471 for (M + H) ⁺;

1 H NMR (CDCl₃) δ :
7.26-6.6 (m, 5.37 (dd, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.71 (s, 3H), 3.56 (s, 3H), 2.47 (d, 2H), 1.58 ( m, 2H).

A more polar fraction and is also isolated identified it as the corresponding trans-lactone.

Example 83 4,4'-difluoro-2,2'-dimethylbenzophenone

3-Fluorotoluene (1 g of a total of 10 g, 90.0 mmol) is added to a well-stirred mixture of aluminum chloride (6.1 g, 46.0 mmol) in carbon tetrachloride (14 ml) at 0 ° C and the mixture is stirred 10 mins. The rest of the 3-fluorotoluene in 9 ml carbon tetrachloride is added and the mixture is stirred at 0 ° C. for 4 hours. The mixture is cooled to -20 ° C. and hydrolyzed by adding 25 ml of 1N hydrochloric acid. The organic layer is separated off and concentrated in vacuo. The residue is stirred for 16 hours with a mixture of benzene (20 ml), water (20 ml) and acetic acid (5 ml). The aqueous layer is separated off and extracted with diethyl ether. The combined organic fractions are dried (MgSO₄) and concentrated in vacuo. The analytical DC of the residue showed 3 spots; R _f = 0.67, 0.59 and 0.56 (5% (v / v ethyl acetate in hexane on silica gel)). Silica gel column chromatography with 0.5% (v / v) ethyl acetate in hexane and collecting the respective fractions containing the substance with R _f = 0.67 (5% (v / v ethyl acetate in hexane)), gives 1.3 g of Title link; FP = 50-52 ° C. MS (CI): m / e = 247 for (M + H) ⁺;

1 H NMR (CDCl₃) δ :
7.26 (2H, dd), 6.96 (2H, dd), 6.87 (2H, dt), 2.42 (6H, s).

Elemental analysis for C₁₅H₁₂F₂O:

calculated: C 73.17%; H 4.92% found: C 73.34%; H 5.02%

Example 84 2,4'-difluoro-4,2'-dimethylbenzophenone

Concentration of the respective fractions of the silica gel column chromatography from Example 83 with the substance with R _f = 0.59 gives 2.4 g of the title compound;
FP = 29-31 ° C. MS (CI): m / e = 347 for (M + H) ⁺;

1 H NMR (CDCl₃) w :
7.53 (1H, t), 7.39 (1H, dd), 7.19-6.85 (4H, m), 2.42 (3H, s), 2.39 (3H, s).

Elemental analysis for C₁₅H₁₂F₂O:

calculated: C 73.17%; H 4.92% found: C 73.34%; H 4.86%

Example 85 2,2'-difluoro-4,4'-dimethylbenzophenone

Concentration of the respective fractions of the silica gel column chromatography from Example 83 with the substance with R _f = 0.56 and trituration of the residue with hexane gives 1.2 g of the title compound;
FP = 84-85.5 ° C.

1 H NMR (CDCl₃) δ :
7.57 (2H, t, J _HH = 8 Hz, J _FH = 8 Hz), 7.02 (2H, d, J _HH = 8 Hz), 6.89 (2H, d, J _FH = 8 Hz), 2.39 (6H, s ).

Elemental analysis for C₁₅H₁₂F₂O:

calculated: C 73.17%; H 4.92% found: C 73.19%; H 4.88%

Example 86 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H- tetrazol 5-yl) ethanol

To a suspension of 1,5-dimethyltetrazole (3.8 g, 39.0 mmol) in tetrahydrofuran (40 ml) are added -40 ° C butyllithium (17.7 ml of a 2.2M solution, 39.0 mmol). Stir it for 10 minutes, give 4,4'-Di fluoro-2,2'-dimethylbenzophenone (8 g, 32.5 mmol) and stir the solution for 3 hours. The reaction is quenched with 1N hydrochloric acid. The aqueous layer is separated off and extracted with ethyl acetate. The combined organic phases are dried (MgSO₄) and concentrated in vacuo and yield 7.5 g of the title compound; M.P. = 186-188 ° C.

Elemental analysis for C₁₈H₁₈F₂N₄O:

calculated: C 62.99%; H 5.27%; N 16.27% found: C 63.01%; H 5.34%; N 16.18%

Example 87 1,1-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H- tetrazol-5-yl) ether

A mixture of 1,1-bis- (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ethanol (0.5 g, 1.5 mmol) and p-toluenesulfonic acid (0.2 g) is refluxed in Toluene (30 ml) heated for 16 hours. The mixture will cooled, diluted with diethyl ether (50 ml) and with saturated sodium bicarbonate solution and Water extracted. The organic layer is dried (MgSO₄) and in Vacuum concentrated. You rub the residue with Diethyl ether and receives 0.3 g of the title compound; M.P. = 120-125 ° C.

Elemental analysis for C₁₈H₁₆F₂N₄:

calculated: C 66.25%; H 4.95%; N 17.17% found: C 66.55%; H 4.92%; N 16.84%

Example 88 3,3-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H- tetrazol-5-yl) -2-propenal

A solution of 1,1-bis (4-fluoro-2-methyl is added phenyl) -2- (1-methyl-1H-tetrazol-5-yl) ether (1.6 g, 5.0 mmol) in tetrahydrofuran butyllithium (2.3 ml of a 2.2M solution, 5.0 mmol) at -70 ° C. The mixture is stirred for 0.25 hours and add ethyl formate (0.44 g, 6.0 mmol) and stir the mixture 2 hours. The reaction is with 1N hydrochloric acid quenched and the mixture is mixed with methylene chloride extracted: the extracts are dried and in vacuo concentrated to give 1.0 g of the title compound; M.P. = 135-136 ° C.

Elemental analysis for C₁₉H₁₆F₂N₄O:

calculated: C 64.41%; H 4.56%; N 15.82% found: C 64.22%; H 4.59%; N 15.50%

Example 89 5,5-bis (4-fluoro-2-methylphenyl) -4- (1-methyl-1H tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (0.88 g, 2.5 mmol) and triphenylphosphoranylidene acetaldehyde (0.75 g, 2.5 mmol) in benzene (50 ml) is heated under reflux for 3 hours. The solvent is removed by evaporation and the tube residue is purified by silica gel column chromatography and eluted with 1% (v / v) methanol in methylene chloride. The fractions containing the substance with R _f = 0.9 (1:20 (v / v) methanol-methylene chloride) are combined and concentrated to give 0.8 g of the title compound; FP = 75-95 ° C. MS³: M⁺ = 380;

1 H NMR (CDCl₃) δ :
9.52 (1H, d), 7.30-6.67 (7H, m), 5.82 (1H, dd), 3.62 (3H, s), 2.23 (3H, s), 2.00 (3H, s).

Elemental analysis for C₂₁H₁₈F₂N₄O:

calculated: C 66.31%; H 4.78%; N 14.73% found: C 65.76%; H 4.85%; N 14.52%

Example 90 tert-butyl 9,9-bis (4-fluoro-2-methylphenyl) -5- hydroxy-8- (1-methyl-1H-tetrazol-5-yl) oxo-6,8-nona dienoat

A solution of 5,5-bis (4-fluoro-2-methyl is added phenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal (1.0 g, 2.5 mmol) in tetrahydrofuran at -50 ° C Dianion of t-butylacetoacetate (2.5 ml of a 1M solution, 2.5 mmol), prepared by adding the t-butylacetoacetate (4.0 g, 25.0 mmol) in tetrahydrofuran (4 ml) into one Suspension of sodium hydride (1.0 g 60% dispersion, 25.0 mmol) in tetrahydrofuran at -5 ° C, then cooling to -30 ° C and addition of butyllithium (11.4 ml a 2.2M solution, 25mmol). You stir for 1.5 hours the analytical TLC shows the starting aldehyde and a further 0.5 ml of the dianion solution is added. The Solution is stirred for another half an hour and quenched with 1N hydrochloric acid. The mixture comes with Extracted methylene chloride. The extracts are dried and concentrated in a vacuum. The residue is purified with silica gel column chromatography and eluted with methanol in methylene chloride and gives 0.6 g of the title compound; M.P. = 65-72 ° C.

Elemental analysis for C₂₉H₃₂F₂N₄O₄:

calculated: C 64.68%; H 5.99%; N 10.41% found: C 64.50%; H 5.98%; N 10.16%

Example 91 tert-Butyl (±) erythro-9,9-bis (4-fluoro-2-methyl phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6,8-nonadienoate

To a solution of t-butyl 9,9-bis (4-fluoro-2-methyl phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo- 6,8-nonadienoate (2.5 g, 4.6 mmol) in tetrahydrofuran (30 ml) are added at -5 ° C triethylborane (6.0 ml one 1M solution; 6.0 mmol) and the solution is stirred for 1 hour. It is cooled to -78 ° C. and sodium borohydride is added (0.36 g, 9.0 mmol) and methanol (2 ml). You stir the mixture at -78 ° C for 2 hours and diluted with Hexane (15 ml). The mixture is mixed with 1N hydrochloric acid hydrolyzed. The aqueous layer is separated off and extracted with methylene chloride. The united organic Solutions are dried and concentrated in vacuo. The residue is dissolved in methanol and the solution was stirred for 18 hours. The solution will be concentrated in vacuo and the residue is through Silica gel column chromatography cleaned and with 1% (v / v) methanol eluted in methylene chloride and gives 1.7 g of the title compound as a White dust; M.P. = 75-80 ° C.

1 H NMR (CDCl₃) w :
7.15-6.60 (7H, m), 6.43 (1H, d), 5.26 (1H, dd), 4.42 (1H, m), 4.18 (1H, m), 3.92 (1H, s), 3.64 (3H, s) , 2.39 (2H, d), 2.26 (3H, bs), 2.04 (3H, s), 1.57 (2H, m), 1.43 (9H, s);

Elemental analysis for C₂₉H₃₄F₂N₄O₄:

calculated: C 64.44%; H 6.34%; N 10.37% found (corr. to 0.28% H₂O): C 64.14%; H 6.41%; N 10.16%

Example 92 Sodium (±) erythro-9,9-bis (4-fluoro-2-methylphenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazole -5-yl) -6,8-nona dienoat

To a solution of t-butyl 9,9-bis (4-fluoro-2-methyl phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6,8-nonadienoate (1.65 g, 3.05 mmol) in ethanol (50 ml) sodium hydroxide solution (3.05 ml of a 1N solution, 3.05 mmol) is added and stir the solution at room temperature for 3 hours and at 50 ° C for 1 hour. The solution is concentrated in vacuo and gives 1.3 g of the title compound, which is approximately 1 mole Appears to contain water; F.P. = 215-225 ° C (dec.)

Elemental analysis for C₂₅H₂₅F₂N₄O₄ NaH₂O:

calculated: C 57.26%; H 5.19%; N 10.69% found: C 57.30%; H 5.20%; N 10.00%

Example 93 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetra zol -5-yl) ethanol

To a solution of 1,5-dimethyltetrazole (4.6 g, 4.7 mmol) in tetrahydrofuran (40 ml) are added -50 ° C butyllithium solution (21.4 ml of a 2.2M solution, 4.7 mmol). The mixture is stirred for 10 minutes and a solution is dispensed 2,2'-difluoro-4,4'-dimethylbenzophenone in tetrahydrofuran (15 ml) to. The solution is stirred for 2.5 hours and during during this time the solution is allowed to warm to -10 ° C. The The reaction is quenched by adding 1N hydrochloric acid. The layers are separated and the aqueous layer is extracted with methylene chloride. The United organic fractions are dried (MgSO₄) and evaporates. The residue is triturated with diethyl ether and crystallized from i-propyl acetate and gives 8.0 g of the title compound; M.P. = 150-151 ° C. MS: M⁺ = 344.

Elemental analysis for C₁₈H₁₈F₂N₄O:

calculated: C 62.79%; H 5.27%; N 16.27% found: C 62.84%; H 5.23%; N 16.28%

Example 94 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H- tetrazol-5-yl) ether

A suspension of 1,1-bis (2-fluoro-4-methylphenyl) - 2- (1-methyl-1H-tetrazol-5-yl) ethanol (7.3 g, 21.0 mmol) in toluene (200 ml) with p-toluenesulfonic acid (3 g) mixed and the mixture is refluxed for 14 hours heated. After cooling, the mixture with diethyl ether diluted and with saturated sodium bicarbonate solution and extracted water. The organic layer is dried (MgSO₄) and evaporated. The residue is with i-propyl ether triturated and gives the title compound; M.P. = 58-60 ° C.

Elemental analysis for C₁₈H₁₆F₂N₄:

calculated: C 66.25%; H 4.95%; N 17.17% found: C 66.27%; H 4.94%; N 16.93%

Example 95 3,3-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetra zol-5-yl) -2-propenal

To a solution of 1,1-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) ether (1.6 g, 5.0 mmol) in Tetrahydroform (20 ml) is added at -78 ° C butyllithium (2.3 ml of a 2.2M solution, 5 mmol). You stir for 15 minutes add ethyl formate (0.44 g, 6.0 mmol) and the solution is stirred with cooling for 2 hours. The reaction is quenched with 1N hydrochloric acid and the mixture extracted with diethyl ether. The extracts are dried (MgSO₄) and evaporated. The backlog will crystallized from i-propyl acetate to give 0.66 g the title compound; M.P. = 154-155 ° C.

Elemental analysis for C₁₉H₁₆F₂N₄O:

calculated: C 64.41%; H 4.56%; N 15.82% found: C 64.44%; H 4.63%; N 15.58%

Example 96 5,5-bis (2-fluoro-4-methylphenyl) -4- (1-methyl-1H- tetrazol-5-yl) -2,4-pentadienal

A solution of 3,3-bis (2-fluoro-4-methylphenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propenal (1.35 g, 3.8 mmol) and triphenylphosphoranylidene acetaldehyde (1.16 g, 3.8 mmol) and benzene is heated under reflux for 3 hours. The solvent is removed and the residue is purified by silica gel column chromatography and eluted with 1% (v / v) methanol in methylene chloride. The fractions containing the substance with R _f = 0.9 (methanol-methylene chloride; 1:20 (v / v)) are combined and concentrated to give 1.3 g of the title compound. FP = 88-108 ° C.

Elemental analysis for C₂₁H₁₈F₂N₄O:

calculated: C 66.31%; H 4.78%; N 14.73% found: C 66.34%; H 4.96%; N 14.37%

Example 97 tert-butyl 9,9-bis (2-fluoro-4-methylphenyl) -5-hydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate

To a solution of 5,5-bis (2-fluoro-4-methylphenyl) - 4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal (1.3 g, 3.4 mmol) in tetrahydrofuran (15 ml) are added -50 ° C the dianion of t-butylacetoacetate (3.4 ml one 1M solution, 3.4 mmol). Stir for 2 hours, give more 0.7 ml of the dianion solution and stir the solution another hour. The reaction is with 1N hydrochloric acid quenched and the mixture with methylene chloride extracted. The extracts are dried (MgSO₄) and focused. The residue is removed using a Silica gel column chromatography purified and with 1% (v / v) eluted methanol in methylene chloride and gave 1.3 g of the title compound; M.P. = 55-63 ° C.

1 H NMR (CDCl₃) δ :
7.05-6.53 (7H, m); 5.28 (1H, dd), 4.60 (1H, m), 3.75 (3H, s), 3.35 (2H, s), 3.05 (1H, bs), 2.69 (2H, d), 2.39 (3H, s), 2.33 (3H, s), 1.45 (9H, s).

Elemental analysis for C₂₉H₃₂F₂N₄O:

calculated: C 64.68%; H 5.99%; N 10.41% found (corr. by 0.21% H₂O): C 64.33%; H 6.07%; N 10.21%

Example 98 t-Butyl (±) -erythro-9,9-bis (2-fluoro-4-methylphenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nona dienoat

To a solution of t-butyl 9,9-bis (2-fluoro-4-methyl phenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo- 6,8-nonadienoate (1.3 g, 2.4 mmol) in tetrahydrofuran triethylborane (3.1 ml of a 1M solution, 3.1 mmol). The mixture is stirred at -5 ° C. for 1 hour and cooled the solution to -75 ° C and gives sodium borohydride (0.2 g, 4.8 mmol) and methanol (1 ml). You stir at -75 ° C for 2 hours, dilute the mixture with 10 ml Hexane and hydrolysed with excess 1N hydrochloric acid. The aqueous layer is separated off and with methylene chloride extracted. The combined organic solutions are dried (MgSO₄) and concentrated in vacuo. The residue is dissolved in methanol and the solution was stirred at room temperature for 19 hours. The solution is concentrated in vacuo and gives 0.6 g of the title compound as a white powder. M.P. = 73-77 ° C.

Elemental analysis for C₂₉H₃₄F₂N₄O₄:

calculated: C 64.44%; H 6.34%; N 10.37% found: C 64.07%; H 6.45%; N 9.78%

Example 99 Sodium (±) -erythro-9,9-bis (2-fluoro-4-methylphenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nona dienoat

To a solution of t-butyl 9,9-bis (2-fluoro-4-methyl phenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6,8-nonadienoate (0.6 g, 1.1 mmol) in ethanol (20 ml) sodium hydroxide solution (1.1 ml of a 1N solution, 1.1 mmol) is added and stir the solution at room temperature for 3 hours and at 50 ° C for 1 hour. The solution is concentrated in vacuo and gives 0.44 g of the title compound, which appears to contain about 1 mole of water; F.P. = 200-205 ° C (dec.)

Elemental analysis for C₂₅H₂₅F₂N₄O₂ NaH₂O:

calculated: C 57.26%; H 5.19%; N 10.69% found: C 57.00%; H 5.27%; N 10.05%

Example 100 Sodium (3R, 5S) -9,9-bis (4-fluorophenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoate A. (1S) -2-hydroxy-1,2,2-triphenylethyl (3S) -7,7-bis- (4-fluorophenyl) -3-hydroxy-6- (1-methyl-1H-tetrazole- 5-yl) hepta-4,6-dionate

A solution of di-i-propylamine (5.33 ml, 3.85 g, 38.1 mmol) in dry tetrahydrofuran (40 ml) is cooled to 0 ° C and with butyllithium (15.2 ml of a 2.5M solution treated in hexane, 38 mmol); the mixture is allowed to warm to 23 ° C over 15 minutes. This solution is cooled to -78 ° C and made into a suspension of (S) - (-) - 1,2,2-triphenyl-2-hydroxyethyl acetate (5.07 g, 19.2 mmol) (prepared according to the process described in Tetrahedron Letters, 5031-5034 (1984)) in dry tetrahydrofuran (40 ml) at -78 ° C. The resulting orange solution is cooled to -78 ° C. and mixed with a solution of 5,5-bis (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -2,4-pentadienal (8 g, 22.73 mmol) in dry tetrahydrofuran (30 ml). The mixture is stirred at -78 ° C for 20 minutes, the reaction is quenched with 2N HCl (80 ml) and the solvent is removed by evaporation. The residue is extracted with ethyl acetate (3 × 50 ml) and the combined organic layers are dried (MgSO₄) and evaporated in vacuo. The residue is purified by silica gel column chromatography using 30% (v / v) ethyl acetate-hexane as the eluent to obtain 9.4 g (90% based on the chiral acetate) of the title compound. [ α ] _D = -41.1 ° (c = 1.16; CH₂Cl₂).

1 H NMR (DMSO-d₆) δ :
7.45-6.80 (m, 23H), 6.54 (s, 1H), 6.50 (d, J = 16.0 Hz, 1H), 6.05 (s, 1H), 5.15 (dd, J = 15.6 Hz, J ′ = 5.2 Hz, 1H), 5.02 (d, J = 5.3 Hz, 1H), 4.33 (m, 1H), 3.70 (s, 0.3H minor diastereoisomer), 3.65 (s, 2.7H major diastereoisomer, 2.29 (m, 2H).

13 C NMR (DMSO-d₆) δ :
194.01, 170.16, 169.32, 163.64, 163.16, 160.36, 159.90, 153.00, 147.77, 145.95, 145.09, 144.50, 138.00, 136.88, 136.42, 135.40, 133.04, 132.28, 131.76, 131.00, 128.54, 127.38, 127.05, 126.61, 126.44, 125.74, 121.40, 115.94, 115.60, 115.40, 115.06, 78.74, 78.36, 67.50 (minor diastereomer), 66.75 (major diastereomer), 59.67, 41.97, 33.47, 20.68, 14.01.

B. Methyl (3S) -7,7-bis (4-fluorophenyl) -3-hydroxy-6- (1-methyl-1H-tetrazol-5-yl) hepta-4,6-dienoate

To a solution of the triphenyl ester, prepared in step A (9.4 g, 13.74 mmol) in dry methanol (40 ml), a solution of sodium metal (2.1 g, 91 mmol) in dry methanol (300 ml) is added and the mixture obtained is stirred at 23 ° C. for 30 minutes. The reaction is quenched with 2N 75905 00070 552 001000280000000200012000285917579400040 0002003805801 00004 75786 HCl (100 ml) and the solvent removed by evaporation. The residue is diluted with water (100 ml) and extracted with ethyl acetate (3 × 70 ml). The combined organic layers are dried (MgSO₄) and evaporated. The residue is purified by silica gel column chromatography using 40% (v / v) ethyl acetate-hexane as solvent to obtain 4.08 g (70%) of the title compound. [ α ] _D = + 28.94 ° (c = 0.85; CH₂Cl₂).

Example 101 Ethyl 1-methyl-5-tetrazolylacetate

To a solution of 1,5-dimethyltetrazole (10 g) in 100 ml dried tetrahydrofuran and 20 ml hexamethylphosphoramide were at -78 ° C (dry ice / acetone) under a Argon atmosphere 50 ml (1.2 equivalents) of n-butyllithium (2.5M in hexane) added. The deprotonation of 1,5-Dimethyltetrazole was at -78 ° C for 40 min and then carried out at -20 ° C for 30 min. The solution of the Anions were cooled again to -78 ° C and then over a Cannula into a cold (-78 ° C) over a period of 45 min Solution of 12 ml ethyl chloroformate in 50 ml tetrahydrofuran transferred. The reaction mixture was aqueous 2N HCl and a saturated aqueous solution of Diluted sodium chloride and then extracted with ethyl acetate. The residue obtained from the organic extract was purified by silica gel flash chromatography. The corresponding Fractions were pooled and evaporated, whereby 4 g of the product were obtained. The product was further purified by crystallization from ethyl acetate / hexane, whereby 3.52 g (21%) of the title compound were obtained; Mp = 64-66 ° C.

Elemental analysis for C₆H₁₀N₄O₂:

calculated: C 42.35%; H 5.92%; N 32.92% found: C 42.40%; H 5.98%; N 33.15%

Example 223 Ethyl-3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - 2-propenoate

A mixture of titanium tetrachloride (2 ml) and carbon tetrachloride (2 ml) was added to 15 ml of tetrahydrofuran at -78 ° C and under an argon atmosphere. The suspension was stirred at -78 ° C for 30 minutes before 0.2 g of 4,4'-difluorobenzophenone was added. After stirring for a further 30 minutes, a solution of 0.15 g of ethyl 1-methyl-5-tetrazolylacetate in 1 ml of dry pyridine was added dropwise. The dark, brownish suspension was stirred at -78 ° C for 15 minutes and then warmed to 0 ° C to form a thick paste. The mixture was left at room temperature for 24 hours before being placed in water. The aqueous mixture was extracted with ethyl acetate to give the crude product. Analytical TLC, developed 5 times with 20% (v / v) ethyl acetate in hexane, showed the desired product at R _f = 0.3. Purification by preparative chromatography on two 20 x 20 cm² 0.25 mm TLC plates, developed twice with 20% (v / v) ethyl acetate in hexane, gave the title compound, which was identical to the compound from Example 3, Step A.

Example 103 Erythro-9,9-bis (fluorophenyl) -3,5-dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid hydrate A. 5,5-bis- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal

A mixture of 448 g (1.37 mol) of 3,3-bis (4-fluorophenyl) - 2- (1-methyl-1H-tetrazol-5-yl) -2-propenal and 445 g (1.46 mol) Triphenylphosphoranylidene acetaldehyde in 5.5 L of toluene heated to 55 ° C with stirring. After switching off the heating source the temperature rose to 62 ° C. After 20 minutes again warmed and held at 60 ° C for 30 min. Analytical TLC (50% ethyl acetate in hexane) indicated the end of the reaction. Lithium bromide (128 g; 1.47 mol) was added and that Mixture stirred at 60 ° C for 1 h. The reaction mixture was filtered and the filtrate under reduced pressure concentrated. The residue was boiling in 900 ml absolute ethanol dissolved. 900 ml were added to this solution Hexane slowly added. After 16 h at room temperature and 2 hours at freezer temperature the mixture was filtered, 418 g (86.6%) of the title compound being exploited were; Mp = 161-165 ° C.

Elemental analysis for C₁₉H₁₄N₄F₂O:

calculated: C 64.77%; H 4.00%; N 15.90% found: C 64.94%; H 3.97%; N 15.82%

B. tert-butyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate

A solution of 144 g (0.91 mol) of tert-butylacetoacetate in 400 ml of tetrahydrofuran was added dropwise over a period of time 1.5 h to a mixture of 44.0 g (1.10 mol) Sodium hydride (60% in mineral oil) in 100 ml hexane and 500 ml Tetrahydrofuran added under nitrogen at 0 ° C. After this addition, this mixture was stirred for 2.3 hours. A 2.5M solution of n-butyllithium in hexane (360 ml; 0.91 mol) was added dropwise over a period of 1 h added. After stirring for 1 hour at 0 ° C, 200 g (0.57 mol) of the aldehyde synthesized in stage A in added to a portion and the temperature rose to 20 ° C at. After stirring for 1 hour in an ice / water bath Spread 1200 ml of a 10% aqueous hydrochloric acid over 1 h added. The organic phase was washed with 2 × 300 ml Water and 300 ml of saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure. The title compound obtained was without reinstalled further cleaning.

C. tert-butyl-erythro-9,9-bis (4-fluorophenyl) -3,6- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

The product from stage B was dissolved in 1 liter of tetrahydrofuran and with 908 ml (0.908 mol) of 1.0M triethylborane in tetrahydrofuran distributed over a period of 45 min. Air was blown into the solution for 5 minutes, causing a lighter colored solution was created. The so obtained Solution was stirred at room temperature for 2 hours. The mixture was cooled to -74 ° C and with 4.0 g of sodium borohydride transferred. After 15 minutes there is a further addition of 32.0 g (36.0 g total; 0.951 mol) sodium borohydride. After stirring for 1 hour, 540 ml of methanol were cautious added over a period of 1.5 h. The reaction mixture was diluted with 540 ml of an aqueous hydrochloric acid and then stirred for 16 h at room temperature. Water (200 ml) was added and the organic solvent under reduced pressure removed. The aqueous mixture was with 2 × 500 ml of methylene chloride extracted, combined and with Washed 2 × 400 ml of water. The organic phase was evaporated at reduced pressure. The one received Title compound was next without further purification Step used.

D. Erythro-9,9-bis (fluorophenyl) -3,5-dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid hydrate

The product from stage C was dissolved in 1 l of 95% ethanol, treated with 1 l of 1N aqueous sodium hydroxide solution and stirred at room temperature for 60 h. This approach was diluted with 2 l of water and then with 2 × 800 ml of hexane as well Washed 2 × 800 ml of diethyl ether. To the stirred aqueous Phase was added dropwise 1.04 l of 1N hydrochloric acid added a period of 4 hours. The mixture became filtered, washed with water and dried, whereby 245 g (91%) of the title compound is exploited as a monohydrate were; Mp = 111-120 ° C (decomposition).

Elemental analysis for C₂₃H₂₂F₂N₄O₄ · H₂O:

calculated: C 58.22%; H 5.10%; N 11.81%; H₂O 3.80% found: C 59.28%; H 5.12%; N 11.53%; H₂O 3.02%

A sample was recrystallized from 50% aqueous methanol. The solution was slowly cooled at 74 ° C and inoculated. After stirring for 16 hours at ambient temperature the solid constituents filtered off with 50% aqueous Washed methanol and air dried, the Title compound was obtained; Mp = 107-115 ° C. This The product was recrystallized from 90% aqueous ethyl acetate. The solution was slowly cooled at the reflux temperature and inoculated at 50 ° C. After stirring at room temperature over a period of 16 h the firm Isolated residue, with cold aqueous ethyl acetate solution washed and air dried, after which the title compound was obtained; Mp = 122-128 ° C (decomposition).

Example 104 Sodium (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

To a hot solution of erythro-9,9-bis (4-fluorophenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadiene carboxylic acid hydrate (20.0 g; 42 mmol) in 200 ml of 2-propanol 3.0 g of potassium hydroxide in 50 ml of 2-propanol was added. The The mixture was evaporated under reduced pressure and the Residue taken up in 100 ml of 2-propanol, cooled and decant the solvent. The residue was then in 100 ml of 2-propanol dissolved, heated to reflux temperature and stirred while the solution was gradually brought to ambient temperature cooled down. After 3 h the solid components filtered off, washed with 2-propanol and in Vacuum dried at 50 ° C. The product was pulverized and dried at 82 ° C under high vacuum for 16 hours, whereby 10.5 g of the title compound were obtained; Mp = 131-145 ° C (Soften at 127 ° C).

Elemental analysis for C₂₃H₂₁N₄O₄F₂K · 3 H₂O:

calculated: C 55.26%; H 4.36%; N 11.21%; H₂O 1.08% found: C 55.44%; H 4.47%; N 11.05%; H₂O 1.38%

Example 105 Trans-6- [4,4-bis- (4-fluorophenyl) -3- (1-methyl-1H-tetrazole- 5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one Method A

A mixture of 308 g (0.649 mol) of the in Example 103 prepared acid and 149 g (0.724 mol) Dicyclohexylcarbodiimide in 6.2 l of ethyl acetate was added Room temperature stirred. After 6 h the mixture became filtered and the solvent under reduced pressure away. This residue, taken up in 500 ml of toluene, was obtained with a similar residue in 500 ml of toluene from a second experiment using 310 g of the acid from Example 103 and 148 g of dicyclohexylcarbodiimide, united. The combined solutions were diluted with 1 liter of toluene and heated to 60 ° C. after the inoculated mixture was stirred for 5.5 hours the residue was filtered off, washed with 300 ml of toluene and air dried. 446 g of the title compound were obtained (78.2%) exploited; Mp = 146-148 ° C.

Elemental analysis for C₂₃H₂₀F₂N₄O₃:

calculated: C 63.01%; H 4.60%; N 12.78% found: C 62.93%; H 4.81%; N 12.78%

Method B

A mixture of 4.3 g of that in Example 103 Synthesized acid in 40 ml of toluene was brought to reflux heated and the water formed by a Dean Stark apparatus removed. After 5 hours, the product filtered off, washed with toluene and air dried. It 3.5 g of the title compound were obtained; Mp = 151-154 ° C.

Elemental analysis for C₂₃H₂₀F₂N₄O₃:

calculated: C 63.01%; H 4.60%; N 12.78% found: C 62.78%; H 4.64%; N 12.72%

Example 106 Ethyl-3,3-bis (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H- tetrazol-5-yl] -2-propenoate

To a solution of 0.64 g (16 mmol) 50% sodium hydride in 7.5 ml of dried dimethylformamide were 4.7 g (16 mmol) Ethyl-3,3-bis- (4-fluorophenyl) -2- (1H-tetrazol-5-yl) -2- propenoate was added and the resulting mixture was Stirred for 30 min. The resulting solution became 5.7 g (18 mmol) bromotriphenylmethane added and that The mixture was stirred for 24 hours. The mixture was mixed with Diluted water to 200 ml and the insoluble components were filtered off. The product was recrystallized from ethyl acetate, whereupon 6.1 g of the title compound are obtained were; Mp = 161-162 ° C (decomposition).

Elemental analysis for C₃₇H₂₈F₂N₄O₂:

calculated: C 74.24%; H 4.72%; N 9.36% found: C 74.31%; H 4.74%; N 9.63%

Example 107 3,3-bis- (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H-tetrazole- 5-yl] -2-propenol

To a stirred solution of 3 g (5 mmol) of ethyl 3,3-bis- (4- fluorophenyl) -2- [2-triphenylmethyl-2H-tetrazol-5-yl] -2- propenoate in 50 ml methylene chloride were 10 ml at -70 ° C (15 mmol) of a diisobutyl aluminum hydride solution (1.5M in methylene chloride) and the solution was stirred for 3 hours. The reaction was quenched with water and the mixture extracted with methylene chloride. The united organic Phases were dried with magnesium sulfate and in Concentrated in vacuo to give 2.1 g of the title compound were; Mp = 176-178 ° C.

Elemental analysis for C₃₅H₂₆F₂N₄O:

calculated: C 75.53%; H 4.71%; N 10.07% found: C 75.75%; H 4.57%; N 10.22%

Example 108 3,3-bis- (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H-tetrazole- 5-yl] -2-propenal

To a solution of 2.2 g (4.0 mmol) of 3,3-bis (4-fluorine phenyl) -2- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -2-propenol 7 g of activated manganese dioxide were added to 100 ml of methylene chloride added. After the resulting mixture After being stirred for 20 hours, insolubles became filtered off and the filtrate concentrated in vacuo, whereby obtained the title compound in quantitative yield has been; Mp = 208 ° C (decomposition).

Elemental analysis for C₃₅H₂₄F₂N₄O:

calculated: C 75.81%; H 4.37%; N 10.11% found: C 73.56%; H 4.44%; N 9.54%

Example 109 5,5-bis- (4-fluorophenyl) -4- [2- (triphenylmethyl) -2H-tetrazole- 5-yl] -2,4-pentadienal

To a solution of 1.75 g (3.15 mmol) of 3,3-bis (4-fluor phenyl) -2- [2- (triphenylmethyl) -2H-tetrazol-5-yl) -2-propenal in 50 ml of dried benzene 0.96 g (3.15 mmol) Triphenylphosphoranylidin-acetaldehyde added and the Solution heated to reflux for 96 hours. The solution was concentrated in vacuo and the residue passed through Chromatography on aluminum oxide (Alcoa Chemicals, Grade F-20) with 10% ethyl acetate in hexane as eluent cleaned. After concentration of the corresponding fractions 0.95 g of the title compound were obtained; Mp = 122-124 ° C.

Elemental analysis for C₃₇H₂₆F₂N₄O:

calculated: C 76.54%; H 4.52%; N 9.65% found: C 75.84%; H 4.86%; N 9.46%

Example 110 tert-butyl-9,9-bis (4-fluorophenyl) -5-hydroxy-3-oxo-8- [2- (triphenylmethyl) -2H-tetrazol-5-yl] -6,8-nonadienoate

A solution of the dianion of tert-butylacetoacetate (1.2 ml of a 0.5M solution; 0.6 mmol) (synthesized according to the procedure of Example 90) was converted into a solution of 5,5-bis (4-fluorophenyl) -4- [2- (triphenylmethyl-2H-tetrazol-5-yl] -2,4-pentadienal in tetrahydrofuran at -70 ° C. After a stirring time of 2.5 h at -70 ° C., the reaction was carried out with a quenched saturated solution of ammonium chloride. The mixture was extracted with diethyl ether, the ether solution dried (MgSO₄) and concentrated in vacuo. The title compound formed in oily form was used without further purification. MS: m / e = 738 for (M⁺).

Example 111 Disodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5- dihydroxy-8- (1H-tetrazol-5-yl) -6,8-nonadienoate A. tert.-butyl- (±) -erythro-9,9-bis- (4-fluorophenyl) - 3,5-dihydroxy-8- [2- (triphenylmethyl) -2H-tetrazol-5-yl] - 6,8-nonadienoate

To a solution of tert-butyl-9,9-bis (4-fluorophenyl) -5- hydroxy-3-oxo-8- [2- (triphenylmethyl) -2H-tetrazol-5-yl] - 6,8-nonadienoate (2.8 g; 3.8 mmol) in tetrahydrofuran at 0 ° C triethylborane (3.8 ml; 1M solution) in tetrahydrofuran added. After stirring for 0.5 h the solution cooled to -70 ° C and sodium borohydride (0.4 g; 10 mmol) and methanol (2 ml) added. To After stirring for 3 h at -70 ° C, the reaction with Quenched water and extracted the mixture with diethyl ether. The extracts were dried over MgSO₄ and in Vacuum concentrated. The viscous residue was dissolved in 100 ml Dissolved methanol and the solution at room temperature over Stirred at night. The methanolic solution was in vacuo concentrated, making 3.0 g of the title compound tougher Residue were exploited. The backlog was in the next stage without further cleaning.

B. tert-butyl- (±) -erythro-9,9-bis- (4-fluorophenyl) - 3,5-dihydroxy-8- (1H-tetrazol-5-yl) -6,8-nonadienoate

A solution of the compound synthesized in step A. (0.8 g; 1.08 mmol) in 50 ml of methanol was treated with 3 ml of 1N HCl acidified. After stirring for 2 hours at room temperature the solution was concentrated in vacuo. The residue was washed several times with hexane and dried in vacuo. 0.5 g of the title compound became tougher Residue exploited and in the next stage without another cleaning step used.

C. Disodium (±) erythro-9,9-bis (4-fluorophenyl) -3,5- dihydroxy-8- (1H-tetrazol-5-yl) -6,8-nonadienoate

The product from stage B was dissolved in 50 ml of ethanol and 2 ml (2 mmol) of 1N sodium hydroxide solution were added. To 16 hours of stirring at room temperature, the solution in Vacuum concentrated. The residue was dissolved in water and extracted with diethyl ether. The aqueous solution became concentrated in vacuo, yielding 0.45 g of the title compound were obtained as dry powder; Mp = 100-105 ° C.

Example 112 Dimethyl- [3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazole- 5-yl) -2-propen-1-yl] phosphonate

A slurry of 3,3-bis (4-fluorophenyl) -2-bromo-2- (1-methyl-1H-tetrazol-5-yl) -2-propene (1.17 g; 3.0 mmol) and trimethyl phosphite (0.41 g; 3.3 mmol) was for 5 min heated to 100 ° C. After cooling to room temperature excess trimethyl phosphite in vacuo to form of a yellow residue. This backlog was recrystallized from an ethyl acetate / hexane mixture, after which obtained the title compound as a pure white residue has been; Mp = 140-141 ° C.

IR (KBr) ν _max :
1604, 1511 cm ^-1 ;

1 H NMR (CDCl₃) δ :
7.7-6.8 (8H, m), 3.6 (3H, s), 3.5 (3H, s), 3.42 (3H, s), 3.2 (2H, d);

Elemental analysis for C₁₉H₁₉F₂O₃N₄P:

calculated: C 54.29%; H 4.56%; N 13.33% found: C 53.83%; H 4.48%; N 13.50%

Example 113 Methyl- (±) -erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate

An equivalent of n-BuLi (2.0 mmol) at -78 ° C. (dry ice / acetone) was added to a solution of the phosphonate (0.84 g; 2.0 mmol) (prepared in Example 112) and the resulting deep red solution was stirred at -78 ° C for 15 min. Methyl erythro-3,5-bis (diphenyl-t-butylsilyloxy) -6-oxohexanoate (synthesized according to the instructions by P. Kapa, et al. In "Tetrahedron Letters", 2435-2438 (1984) and in U.S. Patent 4,571,428 issued February 18, 1986 to P. Kapa) (1.30 g, 2.0 mmol) was added and the mixture was stirred for 24 hours. During this time the reaction mixture was warmed to room temperature. The reaction was quenched by the addition of 5 ml of NH₄Cl and extracted with ethyl acetate (2 × 20 ml). The organic phases were dried (Na₂SO₄) and evaporated to a yellow oil under reduced pressure. The oil was stirred with a 1M solution of tetra-n-butylammonium fluoride in tetrahydrofuran (4 ml) and a few drops of glacial acetic acid for 24 hours. The reaction mixture was poured into water (20 ml) and extracted with methylene chloride (3 x 20 ml). The organic phases were dried (Na₂SO₄), concentrated and the resulting oil was purified by silica gel flash chromatography with ethyl acetate: hexane (2: 1) as the eluent. 0.284 g (41%) of the title compound were obtained in an oily form. MS (CI): m / e = 471 for (M + H) ⁺.

1 H NMR (CDCl₃) δ :
7.26-6.6 (9H, m), 5.29 (1H, dd), 4.42 (1H, m), 4.28 (1H, m), 3.69 (3H, s), 3.54 (3H, s), 2.42 (2H, d) , 1.5 (2H, m).

Example 114 1- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1-phenyl- ethanol

A solution of 1,5-dimethyltetrazole (29.25 g; 0.298 mol) in dry THF (400 ml) was cooled to -78 ° C and with n-butyllithium (133 ml of a 2.5M solution in hexane; 0.3325 mol) reacted for 30 min. The mixture was reacted at -78 ° C for 30 minutes. The mixture was stirred and 4-fluorobenzophenone (50 g; 0.25 mol) was added. The resulting mixture was stirred at -78 ° C for 30 min and warmed to 23 ° C over 2 h. The reaction was quenched with 2N HCl (100 ml) and the organic solvent was evaporated. The residue was extracted with CHCl₃ (2 × 100 ml), the combined organic phases were dried (sodium sulfate) and evaporated to give a brown oil. Chromatographic purification with 20% EtOAc / hexane as eluent gave the title compound as a white solid (46.3 g; 62%). Mp = 113-114 ° C (crystallized from EtOAc / hexane).
MS (CI): m / e = 299 for (M + H) ⁺.

IR (KBr) ν _max :
3300 (br), 1605, 1510 cm ^-1 ;

1 H NMR δ :
7.34-7.15 (m, 7H), 6.93 (m, 2H) 4.93 (s, 1H), 3.73 (s, 2H), 3.67 (s, 3H) ppm;

13 C NMR δ :
163.57, 160.29, 152.28, 144.94, 141.12, 141.08, 128.43, 127.87, 127.75, 127.67, 125.76, 115.25, 114.96, 77.03, 35.82, 33.45 ppm;

Elemental analysis for C₁₆H₁₅FN₄O:

calculated: C 64.42%; H 5.07%; N 18.79% found: C 64.32%; H 5.05%; N 18.84%

Example 115 (E) -1- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1- phenylethene and (Z) -3- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -1- phenylethene

A mixture of tetrazolylethanol (3.2 g; 10.74 mmol) (prepared in Example 114) and potassium hydrogen sulfate (800 mg) were heated to 195 ° C for 30 minutes. After cooling to 100 ° C, chloroform (30 ml) was added and the mixture was stirred until most of the solid was dissolved. The insoluble inorganic material was filtered off and the solvent evaporated to give a mixture of the title compounds as a light brown solid (2.8 g; 93%). Crystallization from EtOAc / hexane.
MS (CI): m / e = 281 for (M + H) ⁺.

IR (KBr) ν _max :
1640, 1600, 1510, 1445, 1220 cm ^-1 ;

1 H NMR w :
7.50-6.90 (m, 9H), 6.75 (s, 1H), 3.60 (s, 1.7H) 3.43 (s, 1.3H) ppm;

13 C NMR δ :
165.19, 164.58, 161.26, 153.14, 152.97, 152.22, 152.13, 140.53, 137.81, 136.71, 133.99, 133.94, 131.74, 131.62, 130.82, 129.67, 129.29, 128.85, 128.65, 128.38, 115.97, 115.74, 115.66, 115.45, 108.29, 108.15, 33.70 ppm;

Elemental analysis for C₁₆H₁₃FN₄:

calculated: C 68.56%; H 4.68%; N 19.99% found: C 68.63%; H 4.77%; N 20.37%

Example 116 (E) -3- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3- phenylpropenal and (Z) -3- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3- phenylpropenal

A suspension of the olefin (20 g; 71.43 mmol) (prepared in Example 115) in dry THF (200 ml) was cooled to -78 ° C and with n-butyllithium (31.5 ml of a 2.5M solution in hexane ; 78.75 mmol) and the resulting mixture was stirred at -78 ° C for 30 min. Ethyl format (6.9 g; 93 mmol) was added, the mixture was stirred at -78 ° C for 2 h and warmed to 23 ° C within 1 h. The reaction was quenched with 2N HCl (100 ml), the organic solvent was evaporated and the residue extracted with EtOAc (3 x 75 ml). The combined organic phases were dried (MgSO₄), evaporated and the residue was purified by chromatography with 35% EtOAc / hexane as the eluent. 7.75 g (35%) of the title compound were obtained as an aldehyde mixture.
MS (CI): m / e = 309 for (M + H) ⁺.

1 H NMR δ :
9.67 (s, 0.66H), 9.64 (s, 0.33H), 7.70-6.90 (m, 9H), 3.74 (s, 1H), 3.68 (s, 2H) ppm;

Example 117 (E), (E) -5- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -5- phenyl-2,4-pentadienal

A mixture of the mixed aldehydes (5.1 g; 16.56 mmol) (prepared in Example 116), formylmethylene triphenylphosphorane (5.05 g; 16.56 mmol) and benzene (200 ml) were combined together under a nitrogen atmosphere for 2 hours Reflux temperature heated. The solvent was evaporated under reduced pressure and the residue was purified by chromatography with 30% EtOAc / hexane as the eluent. The product was obtained as an orange foam (4.56 g). Fractional crystallization from EtOAc / hexane gave the title compound as orange crystals (0.93 g; 17%); Mp = 137-138 ° C (crystallized from EtOAc / hexane).
MS (CI): m / e = 335 for (M + H) ⁺.

1 H NMR δ :
9.54 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 15.6 Hz, 1H), 7.35-6.80 (m, 9H), 5.84 (dd, J = 7.4 Hz, J ′ = 15.7 Hz, 1H) , 3.50 (s, 3H) ppm;

13 C NMR δ :
192.54, 147.86, 132.09, 131.97, 130.64, 130.41, 128.96, 116.17, 115.87, 33.62 ppm.

Example 118 Ethyl- (E), (E) -9- (4-fluorophenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -9-phenyl-3-oxonona-6,8-dienoate

A suspension of sodium hydride (175 mg, 80% dispersion, 5.83 mmol) in dry THF (10 ml) is cooled to 0 ° C. and treated with ethyl acetoacetate (725 μl, 740 mg, 5.69 mmol); the mixture is stirred at 0 ° C. for 10 minutes. Butyllithium (2.3 ml of a 2.5M solution, 5.75 mmol) is added and the mixture is stirred at 0 ° C. for 15 minutes. A solution of the aldehyde (860 mg, 2.57 mmol) (prepared in Example 117) in dry THF (10 ml) is added and the mixture is stirred at 0 ° C for 15 minutes. The reaction mixture is quenched by the addition of 2N HCl (30 ml) and the organic solvent removed by evaporation. The residue is extracted with EtOAc, the combined organic extracts are dried (MgSO₄) and evaporated. The residue is purified by chromatography using 40% EtOAc-hexane as the eluent to give the title compound as a yellow gum (954 mg, 80%).
MS (Ci): m / e = 465 for (M + H) ⁺;

IR (film) ν _max :
3400 (br), 1730, 1600, 1510 cm ^-1 ;

1 H NMR δ :
7.20-6.60 (m, 9H), 6.54 (d, J = 15.6 Hz, 1H), 5.16 (dd, 1H), 4.40 (br, 1H), 4.00 (q and br, 3H), 3.31 (s, 3H) , 3.25 (s, 2H), 2.52 (m, 2H), 1.08 (t, 3H) ppm.

Example 119 Ethyl (±) - (E), (E) -erythro-9- (4-fluorophenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -9-phenylnona-6,8-dienoate

A solution of the β- keto ester (950 mg, 2.045 mmol) (prepared in Example 118) in dry THF (20 ml) is treated with a solution of triethyl borane (2.25 ml of a 1M solution in THF, 2.25 mmol) and Stirred at 23 ° C for 1 hour. Methanol (400 ul) is added, the mixture cooled to -78 ° C and treated with NaBH₄ (200 mg, 5.26 mmol). After 1 hour the reaction mixture is quenched by the addition of 2N HCl and the organic solvent is removed by evaporation. The residue is extracted with EtOAc, the combined organic extracts are dried (MgSO₄) and evaporated. The residue is purified by chromatography using 60% EtOAc-hexane as eluent and to give the title compound as a yellow gum (330 mg, 35%); MS (CI): m / e = 467 for (M + H) ⁺;

IR (KBr) ν _max :
3400 (br), 1725, 1600, 1500 cm ^-1 ;

1 H NMR δ :
7.30-6.80 (m, 9H), 6.70 (dd, J = 1.0 Hz, J ′ = 15.6 Hz, 1H), 5.35 (dd, J = 5.9 Hz, J ′ = 15.7 Hz, 1H), 4.41 (m, 1H ), 4.25 (br s, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.83 (br m, 2H), 3.52 (s, 3H), 2.45 (d, J = 6.1 Hz, 2H), 1.60 (m, 2H), 1.26 (t, J = 6.1 Hz, 3H) ppm;

13 C NMR δ :
172.40, 164.47, 161.17, 153.66, 148.07, 139.94, 138.21, 137.75, 135.55, 132.40, 132.30, 130.36, 129.82, 129.46, 128.67, 128.47, 127.29, 121.05, 115.74, 115.45, 71.89, 69.35, 68.34, 60.83, 60.34, 42.34, 41.53, 41.22, 33.56, 14.13 ppm.

Example 120 Sodium (±) - (E), (E), - erythro-9- (4-fluorophenyl) -3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -9-phenylnona-6,8- dienoate hydrate

A solution of the dihydroxy ester (160 mg, 0.343 mmol) (prepared in Example 119) in EtOH (5 ml) with 1N NaOH (343 ul, 0.343 mmol) treated and the resulting solution stirred at 23 ° C for 1 hour. The solvent is through Evaporation removed and the residue in water (2 ml) dissolved and lyophilized, whereby the title compound as light brown solid obtained (155 mg); M.P. = 130-137 ° C.

IR (KBr) ν _max :
3400 (br), 1560, 1510 cm ^-1 ;

1 H NMR (DMSO-d₆) δ :
7.50-6.80 (m, 9H), 6.51 (d, J = 15.7 Hz, 1H), 5.15 (dd, J = 5.4 Hz, J ′ = 15.7 Hz, 1H), 4.15 (m, 1H), 3.70 (s, 3H), 3.65 (br, 1H), 3.35 (br, 2H), 1.95 (m, 2H), 1.40 (m, 2H) ppm;

13 C NMR (DMSO-d₆) δ :
176.42, 163.42, 153.17, 146.07, 140.03, 139.73, 135.70, 135.64, 132.20, 132.09, 128.72, 128.42, 128.07, 127.98, 124.83, 121.51, 115.51, 115.22, 66.22, 65.69, 44.46, 43.59, 33.42 ppm.

Elemental analysis for C₂₃H₂₂FN₄O₄Na · H₂O:

calculated: C 57.75%; H 5.06%; N 11.72% found: C 58.70%; H 5.10%; N 11.16%

Example 121 2 (1-methyltetrazol-5-yl) -1,1-diphenylethanol

A solution of 1,5-dimethyltetrazole (20 g, 0.204 mol) in dry THF (200 ml) is cooled to -78 ° C. and treated with n-butyllithium (91 ml of a 2.5M solution in hexane, 0.227 mol); the mixture is stirred at -78 ° C for 30 minutes. Benzophenone (31.1 g, 0.171 mol) is added, the mixture is stirred at -78 ° C. for 30 minutes, allowed to come to a temperature of 23 ° C. and stirred for 15 hours. The mixture is quenched with 2N HCl (100 ml) and extracted with EtOAc (3 x 150 ml). The combined organic layers are dried (MgSO₄) and evaporated. The residue is crystallized from EtOAc-hexane to give the title compound as a white solid (10.5 g, 22%); FP = 175-176 ° C; (crystallized from EtOAc-hexane);
MS (CI): m / e = 281 for (M + H) ⁺;

IR (KBr) ν _max :
3300 (br), 1530, 1500 cm ^-1 ;

1 H NMR δ :
7.50-7.20 (m, 1OH), 5.45 (s, 1H), 3.82 (s, 2H), 3.80 (s, 3H) ppm;

13 C NMR δ :
152.36, 145.63, 128.16, 127.28, 126.05, 125.94, 77.70, 35.90, 33.76 ppm;

Elemental analysis for C₁₆H₁₆N₄O:

calculated: C 68.56%; H 5.76%; N 20.00% found: C 68.62%; H 5.81%; N 20.10%

Example 122 2,2-Diphenyl-1- (1-methyl-1H-tetrazol-5-yl) ether

A mixture of 2 (1-methyltetrazol-5-yl) -1,1-diphenylethanol (2.15 g, 7.68 mmol) and KHSO₄ (300 mg) is heated at 200 ° C for 20 minutes. The cooled to 50 ° C mixture is triturated with CHCl₃ (50 ml) and the organic solvent decanted from the inorganic residue. Evaporation gives the title compound as a cream colored solid (1.7 g, 85%); FP = 147-148 ° C; (crystallized from EtOAc-hexane); MS (CI): m / e 0 263 for (M + H) ⁺;

IR (KBr) ν _max :
1640, 1500, 1445 cm ^-1 ;

1 H NMR δ :
7.50-7.00 (m, 10H), 6.78 (s, 1H), 3.43 (s, 3H) ppm;

13 C NMR δ :
153.94, 152.18, 140.40, 137.83, 129.54, 129.37, 128.94, 128.59, 128.38, 128.28, 108.22, 33.56 ppm.

Analysis for C₁₆H₁₄N₄:

calculated: C 73.27; H 5.38 N 21.36 found: C 73.25; H 5.43; N 21.43

Example 123 3,3-diphenyl-2- (1-methyl-1H-tetrazol-5-yl) propenal

A solution of 2,2-diphenyl-1- (1-methyl-1H-tetrazol-5-yl) - ether (3.75 g, 14.29 mmol) in dry THF (40 ml) is brought to -78 ° C cooled and treated with n-butyllithium (6.3 ml of a 2.5 M solution in hexane, 15.75 mmol); the resulting mixture is stirred at -78 ° C for 30 minutes. Ethyl formate (1.5 ml, 18.58 mmol) is added and the mixture is stirred at -78 ° C for 2 hours. The reaction mixture is quenched with 2N HCl and the solvent is removed by evaporation. The residue is extracted with EtOAc (3 × 30 ml) and the combined organic layers are dried (MgSO₄) and evaporated. The residue is purified by chromatography using 25-35% EtOAc-hexane as eluent to give the starting material (1.35 g, 36%) and the desired title compound (1.65 g, 39%); FP = 185-186 ° C; (crystallized from EtOAc-hexane); MS (EI): m / e = 290 for M⁺;

IR (KBr) ν _max :
1675, 1600, 1445 cm ^-1 ;

1 H NMR δ :
9.66 (s, 1H), 7.70-6.90 (m, 10H), 3.66 (s, 3H) ppm;

13 C NMR δ :
189.45, 167.79, 151.44, 138.35, 136.65, 131.54, 131.34, 130.96, 129.63, 128.71, 123.55, 33.91 ppm.

Analysis for C₁₇H₁₄N₄O:

calculated: C 70.34; H 4.87; N 19.30; found: C 70.63; H 4.99; N 19.33.

Example 124 (E) -4- (1-methyl-1H-tetrazol-5-yl) -5,5-bis (phenyl) -2,4- pentadienal

A solution of the aldehyde (1.33 g, 4.57 mmol) (prepared in Example 123) and triphenylphosphoranylidene acetaldehyde (1.5 g, 4.87 mmol) is heated under reflux in benzene (50 ml) for 24 hours. The solvent is evaporated and the residue is purified by chromatography using 30% EtOAc-hexane as eluent and to give the title compound as a yellow foam (1 g, 71%); MS (CI): m / e = 317 (M + H) ⁺;

1 H NMR δ :
9.53 (d, J = 7.5 Hz, 1H), 7.55-7.10 (m, 10H), 6.69 (d, J = 16 Hz, 1H), 5.84 (dd, J = 16 Hz, J ′ = 7.5 Hz, 1H) , 3.50 (s, 3H) ppm.

Example 125 Methyl (E) -9,9-diphenyl-3,5-dihydroxy-8- (1-methyl-1H- tetrazol-5-yl) nona-6,8-dienoate

Methyl acetoacetate (0.525 ml, 4.87 mmol) is added to a suspension of sodium hydride (0.160 g, 80% dispersion in mineral oil) in THF at 0 ° C. and stirred for 10 minutes. Add n-butyllithium (2.14 ml of a 2.5 M solution in hexanes) and stir the reaction mixture for 15 minutes. This solution is added to the solution of the aldehyde (1.0 g, 3.2 mmol) (prepared in Example 124) in THF at 0 ° C and stirred for 30 minutes. The reaction mixture is treated with 2N HCl (30 ml) and extracted with EtOAc (3 × 15 ml). The organic layer is dried with MgSO₄ and evaporated. The tube residue is triturated with hexane (3 × 25 ml), then dissolved in THF / CH₃OH (4: 1, 20 ml) and treated with triethylborane (3.2 ml of a 1 M solution in THF). Air is passed through the solution for 10 minutes and the reaction mixture is stirred for a further 50 minutes. The solution is then cooled to -78 ° C, treated with sodium borohydride (120 mg, 3.2 mmol) and stirred for 1 hour. The reaction mixture is quenched with 2 M HCl (100 ml) and extracted with EtOAc (3 × 20 ml). The organic layers are dried with MgSO₄ and evaporated. The residue is dissolved in CH₃OH (30 ml) and stirred for 15 hours. The solvent is evaporated and the residue is purified by chromatography using 50% EtOAc-hexane as the eluent and to give the title compound as a yellow oil (470 mg, 33%); MS (CI): m / e = 435 (M + H) ⁺;

1 H NMR δ :
7.80-6.80 (m, 10H), 6.71 (d, J = 16 Hz, 1H), 5.34 (dd, J = 16 Hz, J ′ = 6 Hz, 1H), 4.60-4.10 (m, 2H), 3.70 ( s, 3H), 3.52 (s, 3H), 2.45 (d, J = 6 Hz, 2H), 1.70-1.50 (m, 2H) ppm.

Example 126 Sodium (±) - (E) -erythro-9,9-diphenyl-3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoate hydrate

The methyl ester (470 mg, 1.08 mmol) (made in Bei game 125) is dissolved in ethanol (10 ml) and with 1 N NaOH (1.08 ml) treated. The reaction mixture is 1 hour touched. The solvent is evaporated and the residue freeze-dried, using a light yellow powder (500 mg, 100%) receives; M.P. = 145-150 ° C.

IR ν _max :
3400 (br), 1610, 1425, 1360 cm ^-1 ;

1 H NMR (DMSO-d₆) δ :
7.60-6.60 (m, 10H), 6.52 (d, J = 16 Hz, 1H), 5.12 (dd, J = 16 Hz, J ′ = 5.5 Hz, 1H), 4.20-4.05 (m, 1H), 3.80- 3.55 (m, 1H), 3.70 (see 3H), 3.10 (br s, 2H) 2.10-1.10 (m, 5H) ppm.

Analysis for C₂₃H₂₃N₄O₄Na.H₂O:

calculated: C 59.99; H 5.47; N 12.17; found: C 59.18; H 5.46; N 10.96.

Example 127 2,2-bis (4-methoxyphenyl) -1- (1-methyl-1H-tetrazol-5-yl) ether

A solution of 1,5-dimethyltetrazole (20 g, 0.204 mol) in dry THF (200 ml) is cooled to -78 ° C. with n-butyllithium (91 ml of a 2.5 M solution in hexane, 0.227 mol) be and the reaction mixture is stirred at -78 ° C for 30 minutes. 4,4'-dimethoxybenzophenone (41.3 g, 0.171 mol) is added and the mixture is stirred at -78 ° C for 30 minutes; the mixture is allowed to come to a temperature of 23 ° C. for 2 hours. It is acidified with 2N HCl (100 ml) and the organic solvent is removed by evaporation. The residue is extracted with EtOAc (3 × 300 ml), the combined organic layers are dried (MgSO₄) and evaporated. The residue is crystallized from EtOAc-hexane to give a light brown solid (48 g) which is a mixture of the desired product and the initial aldol adduct 1,1-bis (4-methoxyphenyl) -2- (1-methyl- 1H-tetrazol-5-yl) ethanol. This mixture is dissolved in xylene (180 ml) and heated under reflux for 1 hour with p-toluenesulfonic acid in a Dean-Stark apparatus. The cooled mixture is diluted with ether (100 ml) and the resulting solid is collected by filtration to give the title compound as an off-white solid (40 g); FP = 146-147 ° C; (crystallized from EtOAc-hexane); MS (CI): m / e = 323 for (M + H) ⁺;

IR (KBr) ν _max :
1605, 1520, 1250 cm ^-1 ;

1 H NMR δ :
7.31 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.62 ( s, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.42 (s, 3H) ppm;

13 C NMR δ :
160.79, 160.16, 153.29, 133.33, 131.25, 130.32, 129.95, 127.36, 114.14, 113.69, 105.57, 55.40, 55.28, 33.71 ppm.

Analysis for C₁₈H₁₈N₄O₂:

calculated: C 67.07; H 5.63; N 17.38; found: C 66.93; H 5.63; N, 17.05.

Example 128 3,3-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) pro penal

A solution of the olefin (4.6 g, 14.29 mmol) (prepared in Example 127) in dry THF (50 ml) is cooled to -78 ° C and with n-butyllithium (6.3 ml of a 2.5 M Solution in hexane, 15.75 mmol) treated; the resulting solution is stirred at -78 ° C for 30 minutes. Ethyl formate (1.5 ml) is added and the mixture is stirred at -78 ° C for 2 hours. The reaction mixture is quenched with 2N HCl and the organic solvent is removed by evaporation. The residue is extracted with EtOAc (3 × 30 ml), the combined organic layers are dried (MgSO₄) and evaporated. The residue is purified by means of column chromatography, 25-35% EtOAc-hexane being used as the eluent, and the starting substance (0.84 g, 18%) is obtained. The desired title compound (1.78 g, 36%) is obtained by further elution. FP = 130-131 ° C; (crystallized from EtOAc-hexane); MS (CI): m / e = 351 for (M + H) ⁺;

IR (KBr) ν _max :
1675, 1605, 1515, 1260 cm ^-1 ;

1 H NMR δ :
9.59 (s, 1H), 7.30 (d, J = 8.6 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) ppm;

13 C NMR δ :
189.51, 167.47, 162.59, 161.98, 152.30, 133.91, 132.29, 130.79, 129.35, 121.05, 114.20, 114.15, 55.80, 55.40, 33.94 ppm.

Analysis for C₁₉H₁₉N₄O₃:

calculated: C 65.14; H 5.18; N 15.99; found: C 64.96; H 5.22; N, 15.75.

Example 129 5,5-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) penta-2,4-dienal

A solution of 3,3-bis (4-methoxyphenyl) -2- (1-methyl-1H-tetrazol-5-yl) propenal (1.7 g, 4.86 mmol) in benzene (100 ml) is mixed with triphenylphosphoranylidene acetaldehyde (1.55 g, 5.1 mmol) and refluxed for 3 hours. The solvent is removed by evaporation and the residue is purified by chromatography using 30% EtOAc-hexane as the eluent to give the title compound as a yellow foam (1.35 g, 74%). MS (CI): m / e) = 377 for (M + H) ⁺:

IR (KBr) ν _max :
1675, 1590, 1510 cm ^-1 ;

1 H NMR δ :
9.52 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 14.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 9.3 Hz, 1H), 6.86 ( d, J = 9.2 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 5.83 (dd, J = 7.6 Hz, J ′ = 15.7 Hz, 1H), 3.91 (s, 3H), 3.75 (s , 3H), 3.50 (s, 3H) ppm;

13 C NMR δ :
192.89, 161.40, 160.97, 157.91, 153.29, 149.41, 133.90, 132.77, 132.29, 132.00, 131.71, 131.65, 131.25, 130.81, 117.21, 114.18, 114.12, 55.49, 55.32, 33.61 ppm.

Example 130 Ethyl- (E) -9,9-bis (4-methoxyphenyl) -hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxonona-6,8-dienoate

Ethyl acetoacetate (825 µl, 842 mg, 6.48 mmol) is added a suspension of NaH (206 mg, 80% dispersion, 6.86 mmol) in dry THF (20 ml) at 0 ° C and stir the resulting Mix at 0 ° C for 10 minutes. You spend a solution n-butyllithium (2.7 ml of a 2.5 M solution in hexane, 6.75 mmol) and stir the mixture at 0 ° C for 10 minutes. A solution aldehyde (1.3 g, 3.46 mmol) (prepared in Example 129) in dry THF (20 ml) is added and the mixture stirred at 0 ° C for 15 minutes. After adding 2N HCl has to quench the reaction mixture, the solution removed by evaporation. The arrears with Diluted water (30 ml), extracted with EtOAc (2 × 20 ml), and the combined organic layers are dried (MgSO₄) and evaporated. The backlog is by means of Chromatography purified using 40% EtOAc-hexane as Eluent is used and the title compound obtained as a yellow foam (1.165 g, 66%).

IR (KBr) n _max :
3450 (br), 1750, 1710, 1610, 1510 cm ^-1 ;

1 H NMR δ :
7.30-6.60 (m, 9H), 5.27 (dd, J = 6.1 Hz, J ′ = 15.9 Hz, 1H), 4.68 (brs, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.83 (s, 3H) 3.69 (s, 3H), 3.47 (s, 3H), 3.43 (s, 2H), 3.17 (brs, 1H), 2.70 (d, J = 6.0 Hz, 2H), 1.23 (t, J = 6.0 Hz, 3H) ppm;

13 C NMR δ :
202.48, 160.09, 159.70, 154.16, 149.40, 134.16, 132.57, 132.14, 131.99, 131.22, 129.08, 118.34, 113.79, 68.17, 61.47, 55.34, 55.17, 49.94, 49.33, 33.56, 14.09 ppm.

Example 131 Ethyl- (±) - (E) -erythro-9,9-bis (4-methoxyphenyl) -3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoate

A solution of the β- keto ester (1 g, 1.97 mmol) (prepared in Example 130) in dry THF (50 ml) and methanol (300 μl) is mixed with a solution of triethylborane (2.15 ml of a 1 M solution in THF) treated and the mixture stirred at 23 ° C for 1 hour. The solution is cooled to -78 ° C and treated with NaBH₄ (110 mg, 2.92 mmol). After 1 hour the reaction mixture is quenched at -78 ° C with 2N HCl and the solvent is removed by evaporation. The residue is diluted with water and extracted with EtOAc (3 × 30 ml). The combined organic extracts are dried (MgSO₄) and evaporated. The residue is purified by chromatography to give the title compound as a light oil (136 mg).

IR (KBr) ν _max :
3450 (br), 1750, 1710, 1610, 1510 cm ^-1 .

1 H NMR δ :
7.70-6.50 (m, 9H), 5.80 (dd, 1H), 4.45 (br, 1H), 4.15 (q, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.50 (s, 3H) , 2.45 (m, 2H), 1.55 (m, 2H), 1.26 (t, 3H) ppm;

13 C NMR δ :
172.38, 160.16, 159.29, 154.32, 148.92, 138.54, 136.19, 132.81, 132.29, 132.20, 132.11, 131.90, 131.51, 131.22, 128.59, 128.41, 128.36, 118.97, 113.90, 113.34, 72.15, 66.31, 60.75, 55.35, 55.20, 42.74, 42.14, 41.73, 41.48, 33.50, 14.18.

Example 132 Sodium (±) - (E) -erythro-9,9-bis (4-methoxyphenyl) -3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) nona-6,8-dienoate di hydrate

A solution of the ester (95 mg, 0.196 mmol) (made in Example 131) in ethanol (15 ml) with 1 N NaOH solution (196 ul) treated and the mixture ge at 23 ° C for 1 hour stirs. The solvent is removed by evaporation; the residue is dissolved in water (2 ml) and frozen dries, whereby the title compound as a brown powder (95 mg, 100%). M.P. = 175-180 ° C.

IR (KBr) ν _max :
3400 (br), 1600, 1575, 1510 cm ^-1 ;

1 H NMR (DMSO-d₆) δ :
7.70-6.65 (m, 9H), 6.55 (d, J = 15.5 Hz, 1H), 5.08 (dd, J = 5.6 Hz, J ′ = 15.7 Hz, 1H), 4.14 (br, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.66 (s, 3H), 2.10-1.80 (br, 2H), 1.50-1.20 (br, 2H) ppm;

13 C NMR (DMSO-d₆) δ :
159.25, 158.80, 153.78, 138.13, 132.75, 131.88, 131.60, 131.42, 131.30, 130.41, 128.68, 128.53, 125.72, 113.74, 113.48, 68.56, 65.89, 55.14, 54.99, 44.68, 43.68, 33.34.

Analysis for C₂₅H₂₇NaN₄O₆.2H₂O:

calculated: C 55.76; H 5.81; N 10.41; found: C 54.43; H 5.04; N 8.15.

Example 133 Cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester

Methyl 3,5-dihydroxy-7-phenyl-6-enoate (98% diastereomeric Purity) (2.37 g, 9.48 mmol) with 2,2-dimethoxypropane (20 ml) and a catalytic amount of p-toluenesulfone acid stirred for 16 hours. The solution is between diethyl ether and dilute aqueous sodium bicarbonate solution ver Splits. The organic layer is dried (Na₂SO₄) and concentrated under reduced pressure, making one receives yellow solid. After recrystallization i-Propyl ether gives 1.70 g (62%) of the title compound as a white solid. M.P. = 84-86.5 ° C.

Alternatively, you can use 0.2 g of solid sodium carbonate add to the 2,2-dimethoxypropane solution and the solution vigorously stir. The solid is removed using a pleated filter filtered off. The excess 2,2-dimethoxypropane is removed under reduced pressure, one receives yellow solid which recrystallized from i-propyl ether is settled.

1 H NMR (CDCl₃) w :
7.37-7.19 (5H, m), 6.59 (1H, d, J = 15.9 Hz), 6.14 (1H, dd, J = 15.9, 6.4 Hz), 4.57-4.35 (1H, m), 4.42-4.35 (1H, m), 3.68 (3H, s), 2.58 (1H, d, J = 15.6, 6.9 Hz), 2.14 (1H, dd, J = 15.6, 6.3 Hz), 1.74-1.61 (1H, m), 1.52 (3H , s), 1.43 (3H, s), 1.45-1.35 (1H, m).

Analysis for C₁₇H₂₂O₄:

calculated: C 70.32; H 7.63; found: C 70.24; H 7.69.

Example 134 Cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid

A solution of 2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane 4-Acetic acid methyl ester (8.5 g, 29.3 mmol) in 1 N NaOH (32 ml) and methanol (64 ml) are refluxed for 45 minutes heated. After evaporation under reduced pressure, the aqueous solution washed once with diethyl ether and with 1N HCl (33 ml) acidified. The precipitate is filtered off and recrystallized from ethyl acetate / i-propyl ether, wherein 7.2 g (90%) of the title compound as a colorless solid receives fabric. M.P. = 153-155 ° C.

1 H NMR (CDCl₃) δ :
7.37-7.20 (5H, m), 6.60 (1H, d, J = 16.0 Hz), 6.14 (1H, dd, J = 16.0, 6.4 Hz), 4.59-4.54 (1H, m), 4.43-4.35 (1H, m), 2.62 (1H, dd, J = 16.0, 7.2 Hz), 2.51 (1H, dd, J = 16.0, 5.3 Hz), 1.77-1.72 (1H, m), 1.54 (3H, s), 1.46 (3H , s), 1.50-1.36 (1H, m).

Analysis for C₁₆H₂₀O₄:

calculated: C 69.54; H 7.30; found: C 69.20; H 7.33.

Example 135 Splitting of the cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3- dioxane-4-acetic acid

The racemic cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3- dioxane-4-acetic acid (0.31 g, 1.1 mmol) (made in Example 134) is in a boiling solution of hexane / Dissolved ethanol, the (1S, 2R) ephedrine (0.2 g, 1.1 mmol) ent holds. The resulting solution is left on very slowly Come to room temperature, with 0.21 g (41.4%) of one colorless chiral salt (use diastereomerically pure seed crystals are formed during the splitting recommended). M.P. = 170-171 ° C.

The chiral acid is released by working up in acid (see below) and its enantiomeric purity (100%) is determined by 1 H NMR, using L-phenyltrifluoromethylcarbinol as the chiral solvent. [ α ] = + 5.45 ° (c = 1, CHCl₃).

Example 136 Cis- (4R, 6S) -2,2-dimethyl-6-formyl-1,3-dioxane-4-vinegar acid

The split salt of cis-2,2-dimethyl-6- (2-phenyl ethenyl-1,3-dioxane-4-acetic acid and des (1S, 2R) ephedrine (6.6 g, 14.9 mmol) (prepared in Example 135) partitioned between 0.5 N HCl (30 ml) and diethyl ether. The Ether layer is washed with saline, dried (MgSO₄ / Na₂SO₄) and concentrated under reduced pressure, giving 4.1 g (99.6%) of the free acid. These Acid is dissolved in dry methylene chloride (100 ml) and ozone is passed through the solution at -78 ° C until one deep blue coloration occurs. Excess ozone is removed by flushing removed with nitrogen and the ozonide formed decomposed by adding CH₃SCH₃ (5 ml); one leaves the Solution come to room temperature and leave it for 16 hours stand. The solution is concentrated under reduced pressure centered and the residue in the i-amyl ether (approx. 100 ml) solved. The benzaldehyde that occurs during ozonolysis has formed with the i-amyl ether under reduced Distilled off azeotropically, whereby the title compound receives.

1 H NMR (CDCl₃) δ :
9.57 (1H, s), 4.40-4.30 (2H, m), 2.60 (1H, dd, J = 16.0, 7.0 Hz), 2.49 (1H, dd, J = 16.0, 6.0 Hz), 1.88-1.83 (1H, m) 1.49 (3H, s), 1.46 (3H, s), 1.42-1.31 (1H, m).

Example 137 Cis- (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H- tetrazol-5-yl) -1,3-butadienyl] -2,2-dimethyl-1,3-dioxane 4-acetic acid

The crude chiral acid (prepared in Example 136) is dissolved in dry THF (50 ml), the resulting solution placed in a 3 neck flask which was purged with nitrogen and is equipped with a mechanical stirrer. after the Solution was stirred vigorously and cooled to -78 ° C, n-BuLi (2.5 M solution in hexane, 5.96 ml) is added dropwise. Towards the end of the dropping, the solution becomes a Sus board made of white, solid-like gel.

Another flask, the dimethyl [3,3-bis (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -2-propen-1-yl] phosphonate (6.2 g, 14 , 7 mmol) (prepared in Example 112) in THF (50 ml), is cooled to -78 ° C. under a nitrogen atmosphere and slowly added n-BuLi (2.5 M solution in hexane, 5.96 ml). The resulting red-brown solution is stirred for 15 minutes at -78 ° C. This solution of the phosphonate anion is added by means of a cannula with 2 ends to the vigorously stirred suspension mentioned above at -78 ° C., the suspension containing the lithium salt of the chiral acid. After the addition, the resulting brown solution is stirred at -78 ° C for 30 minutes and at room temperature for 16 hours. The THF solution is divided between 0.5 N HCl and ethyl acetate. The organic phase is washed with brine (2 ×), dried (Na₂SO₄) and concentrated under reduced pressure. The residue is chromatographed on silica gel (66: 33: 1 / diethyl ether: hexane: acetic acid) to give 3.80 g of the title compound as a yellow foam (51.6% total of the initial ephedrine salt; toluene is used to remove the to distill off the remaining acetic acid azeotropically). [ α ] = + 106.1 ° (c = 2.23, CHCl₃).

1 H NMR (CDCl₃) δ :
7.24-6.82 (8H, m), 6.62 (1H, d, J = 15.0 Hz), 5.32 (1H, dd, J = 15.0, 5.7 Hz), 4.42-4.37 (1H, m), 4.30-4.23 (1H, m), 3.51 (3H, s), 2.53 (1H, dd, J = 15.9, 7.0 Hz), 2.42 (1H, dd, J = 15.9, 5.6 Hz), 1.62-1.57 (1H, m), 1.46 (3H , s), 1.33 (3H, s), 1.30-1.20 (1H, m).

Example 138 Trans- (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H- tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy-2H- pyran-2-one

Cis- (4R, 6S) -6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] -2,2- dimethyl-1,3-dioxane-4-acetic acid (3.7 g, 7.45 mmol) is dissolved in a solution of THF (90 ml) and 0.2 N HCl (60 ml) and left for 16 hours stand. The solution is partitioned between ethyl acetate and water. The organic layer is washed with brine (2 ×), dried (Na₂SO₄), and concentrated under reduced pressure. The residue is dissolved in dry methylene chloride (60 ml) and stirred for 4 hours in the presence of 1-cyclohexyl-3- (2-morpholine methyl) carbodiimide metho-p-toluenesulfonate (6.6 g, 15.6 mmol). The solution is concentrated under reduced pressure; the residue is partitioned between ethyl acetate and water. The organic layer is dried (Na₂SO₄) and concentrated under reduced pressure. The residue is purified by chromatography on silica gel (1: 1 / ethyl acetate: diethyl ether). After recrystallization from ethyl acetate-hexane, 1.33 g (40.1%) of the title compound is obtained as a white solid. FP = 172-173 ° C. [ α ] = + 237.8 ° (c = 2.17, CHCl₃).

Example 139 Methyl 3-hydroxy-5-oxo-6,8-decadienoate

To a -30 ° C cold solution of methyl acetoacetate (41.5 g, 357 mmol) in THF (500 ml) are added lithium diisopropylamide (476 ml, 1.5 M solution in cyclohexane, 714 mmol). You cool the solution to -78 ° C gives 2,4-hexadienal (34.3 g, 357 mmol) and stir for 10 minutes at -78 ° C and 16 hours in room temperature. The solution is concentrated under reduced pressure and the syrup obtained between 1N HCl and Distributed ethyl acetate. The organic layer is cooked with brine (2 ×) washed, dried (Na₂SO₄) and kon centered. The residue is indicated by chromatography Silica gel (diethyl ether: hexane / 2: 1) cleaned, whereby one 18.5 g (24.4%) of the title compound is obtained as an oil.

1 H NMR for (E) (E) -isomer (200MHz, CDCl₃) δ :
6.3 (1H, dd, J = 14.7, 11.9 Hz), 6.02 (1H, dd, J = 14.7, 11.9 Hz), 5.75 (1H, dq, J = 14.7, 6.4 Hz), 5.5 (1H, dd, J = 18.7, 6.4 Hz), 4.74-4.5 (1H, m), 3.73 (3H, s), 3.51 (2H, s), 2.6 (2H, d, J = 5.8 Hz), 1.77 (3H, d, J = 6.4 Hz).

Example 140 Methyl 3,5-dihydroxy-6,8-decadienoate

To a -15 ° C cold solution of methyl-3-hydroxy-5-oxo 6,8 decadienoate (18.5 g, 86.9 mmol) in THF (300 ml) triethylborane (1 M solution in THF, 113 ml, 113 mmol) and the solution is stirred for 20 minutes. The mixture is cooled -78 ° C and gives NaBH₄ (6 g, 159 mmol) and methanol (37.5 ml) to. The solution is stirred vigorously for 30 minutes at -78 ° C and 3 hours at room temperature. The solvent will removed under reduced pressure and the residue between Distributed 1N HCl and ethyl acetate. The organic layer is dried (Na₂SO₄) and concentrated. The residue is chromatographed on silica gel (diethyl ether: hexane / 3: 1) cleaned, giving 7.95 g (42.7% of the title compound as a yellow oil.

1 H NMR for the (E) (E) isomer (360MHz, CDCl₃) δ :
6.18 (1H, dd, J = 15.1, 10.4 Hz), 6.00 (1H, dd, J = 15.1, 10.4 Hz), 5.69 (1H, dq, J = 15.1, 7.0 Hz), 5.52 (1H, dd, J = 15.1, 6.7 Hz), 4.46-4.37 (1H, m), 4.29-4.22 (1H, m), 3.69 (3H, s), 2.60-2.42 (2H, m), 1.72 (3H, d, J = 7.0 Hz ), 1.74-1.57 (2H, m).

Example 141 Methyl-cis-4- (1,3-pentadienyl) -1,5-dioxaspiro [5,5] undecan- 2-acetate

Methyl 3,5-dihydroxy-6,8-decadienoate (7.6 g, 35.5 mmol) and p-toluenesulfonic acid (0.1 g) to cyclohexanone (10 g, 100 mmol) and stirred for 16 hours at room temperature. The yellow solution is applied directly to a silica gel acid enter and the product eluted with diethyl ether: hexane (1: 4). The respective fractions are combined, giving 3.52 g (33.6%) of the title compound as a colorless oil.

1 H NMR for the (E) (E) isomer (360MHz, CDCl₃) δ :
6.16 (1H, dd, J = 15.1, 10.6 Hz), 6.00 (1H, dd, J = 15.1, 10.6 Hz), 5.71-5.65 (1H, dd, J = 15.1, 6.5 Hz), 5.47 (1H, dd, J = 15.1, 6.4 Hz), 4.44-4.39 (1H. M), 4.35-4.30 (1H, m), 3.66 (3H, s), 2.52 (1H, dd, J = 1.54, 7.9 Hz), 2.30 (1H , dd, J = 15.4, 6.5 Hz), 2.1-1.18 (12H, m), 1.72 (3H, d, J = 6.5 Hz).

Analysis for C₁₇H₂₆O₄:

calculated: C 69.36; H 8.90; found: C 69.59; H 9.16.

Example 142 Cis-4- (1,3-pentadienyl) -1,5-dioxaspiro [5.5] undecane-2-vinegar acid

Methyl-4- (1,3-pentadienyl) -1,5-dioxasprio [5.5] undecan-2- acetate (3.5 g, 12.4 mmol) is refluxed in a Solution of 1N NaOH (13 ml) and methanol (26 ml) heated. Methanol is removed under reduced pressure, which ver remaining aqueous solution is acidified with 1N HCl and extracted with diethyl ether. The organic layer will dried (Na₂SO₄) and concentrated. The solid residue is recrystallized from ethyl acetate-hexane, where 2.0 g (55.9%) of the title compound as a colorless solid receives fabric. M.P. = 144-146.5 ° C.

1 H NMR (360 MHz, CDCl₃) δ :
6.18 (1H, dd, J = 18.0, 12.5 Hz), 5.72, dq, J = 18.0, 7.7 Hz), 5.99 (1H, dd, J = 18.0, 12.5 Hz), 5.48 (1H, dd, J = 18.0, 7.6 Hz), 4.45-4.37 (1H, m), 4.37-4.25 (1H, m), 2.56 (1H, dd, J = 18.9, 8.8 Hz), 2.48 (1H, dd, J = 18.9, 6.1 Hz), 2.60-1.30 (12H, m), 1.73 (3H, d, J = 7.7 Hz).

Analysis for C₁₆H₂₄O₄:

calculated: C 68.54; H 8.62; found: C 68.36; H 8.55.

Example 143 Cis-4- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) - 1,3-butadienyl] -1,5-dioxaspiro [5.5] undecan-2-acetic acid A. 4-Formyl-1,5-dioxaspiro [5.5] undecan-2-acetic acid

A solution of 4- (1,3-pentadienyl) -1,5- dioxaspiro [5.5] undecane-2-acetic acid (570 mg, 2.0 mmol) in Methylene chloride (25 ml) added at -78 ° C. after the Solution has got a blue color, nitrogen will pass through given the solution to remove the excess ozone. Dimethyl sulfide (0.5 ml) is added and the solution under reduced pressure, focusing on the title compound manure as a viscous oil, which without further cleaning is used in the subsequent stage.

1 H NMR (60 MHz, CDCl₃) δ :
9.57 (1H, s), 4.52-4.14 (2H, m), 2.60-2.31 (2H, m), 2.10-1.10 (12H, m).

B. Cis-4 [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazole- 5-yl) -1,3-butadienyl] -1,5-dioxaspiro [5.5] -undecan-2-carboxylic acid

To a solution of dimethyl [3,3-bis- (4-fluorophenyl) -2- (1- methyl-1H-tetrazol-5-yl) -2-propenyl] phosphonate (1.7 g, 4 mmol) in THF (20 ml) are added at -78 ° C. n-BuLi (1.6 ml, 4 mmol, 2.5 M solution in hexane). The resulting brown-red Solution is stirred at -78 ° C for 30 minutes. This solution is added to a solution with a cannula with 2 ends, which is 4-formyl-1,5-dioxaspiro [5.5] undecan-2-acetic acid (prepared in Step A) in THF (10 ml) and on Kept at -78 ° C. After the addition, stir combined reaction mixture at -78 ° C for 1 hour and at Room temperature 4 hours. The solution is then between Distributed 0.5 N HCl and ethyl acetate. The organic layer is washed with brine (2 ×), dried (Na₂SO₄) and concentrated under reduced pressure. The backlog will using chromatography on silica gel (diethyl ether: hexane: vinegar acid / 50: 20: 1), whereby 342 mg (31.9% ins total) of the title compound as a yellow foam.

1 H NMR (360 MHz, CDCl₃) δ :
7.25-6.84 (8H, m), 6.66 (1H, d, J = 16.0 Hz), 5.32 (1H, dd, J = 16.0, 5.10 Hz), 4.45-4.25 (2H, m), 3.52 (3H, s) , 2.56 (1H, dd, J = 16.0, 7.6 Hz), 2.44 (1H, dd, J = 16.0, 5.1 Hz), 1.89-1.17 (12H, m).

Example 144 Trans-6- [4,4-bis (4-fluorophenyl) -3- (1-methyl-1H-tetrazole-5- yl) -1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one

A mixture of 4- [4,4-bis (4-fluorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] -1,5-dioxaspiro [5.5] undecan-2-acetic acid (280 mg, 0.52 mmol) in 20 ml THF / 0.5 N HCl (1: 1) at room temperature for 26 hours. The solution is distributed between saline and ethyl acetate. The organic layer is washed with saline (2 ×) wash, dry (Na₂SO₄) and concentrated. The ent Stand foam (126 mg) in dry methylene chloride (10 ml) dissolved and with 1-cyclohexyl-3- (2-morpholine methyl) treated carbodiimide metho-p-toluenesulfonate (0.24 g). After 16 hours at room temperature the solution is under evaporated under reduced pressure and the residue by means of Silica gel chromatography purified using ethyl acetate as Eluent is used. The respective groups give 38 mg (16.6%) of the title compound as a colorless Oil, which is a racemic mixture of the compound of Example 7 is.

Example 145 Methyl 2,2-dimethyl-6-formyl-1,3-dioxane-4-acetate

Cis-2,2-dimethyl-6- (2-phenylethenyl) -1,3-dioxane-4-acetic acid methyl ester (prepared in Example 133) is in methanol (10 ml) dissolved and ozone is dissolved by the solution at -78 ° C given until the solution turns blue. The reaction mixture is flushed with nitrogen to remove excess ozone distant; then dimethyl sulfide is added and allowed to the solution come to room temperature. The reaction The mixture is evaporated in a vacuum and the remaining oil purified by chromatography on silica gel, where Diethyl ether: hexane (3: 1) is used as the eluent and you get the title compound.

1 H NMR (360 MHz, CDCl₃) δ :
9.53 (1H, s), 4.40-4.23 (2H, m), 3.69 (3H, s), 2.53 (1H, dd, J = 15.8, 7.02 Hz), 2.37 (1H, dd, J = 15.8, 5.98 Hz) , 1.85-1.76 (1H, m), 1.44 (3H, s), 1.40 (3H, s), 1.35-1.23 (1H, m).

Example 146

The general procedures of Example 80, Steps B, C and D and Examples 112, 137 and 138 are below repeated with the exception that 4,4′-difluorobenzophenone, used in Example 80, level B, is replaced by a equimolar amount of

• (a) 2,2 ', 4,4'-tetramethoxybenzophenone
• (b) 3,3 ', 4,4'-tetramethoxybenzophenone
• (c) 2,2 ', 4,4'-tetramethylbenzophenone
• (d) 3,3 ', 4,4'-tetramethylbenzophenone
• (e) 3,3 ', 5,5'-tetramethylbenzophenone
• (f) 4'-fluoro-2,4,6-trimethylbenzophenone
• (g) 2,2'3,3 ', 4,4'-hexamethoxybenzophenone
• (h) 2,2'4.4 ', 6,6'-hexamethylbenzophenone
• (i) 4'-methoxy-2,5-dimethylbenzophenone
• (j) 4'-methoxy-2,4,6-trimethylbenzophenone
• (k) 2,2 ', 4,4'-tetrachlorobenzophenone
• (l) 2,2 ′, 5,5′-tetrachlorobenzophenone
• (m) 2,2 ', 6,6'-tetrachlorobenzophenone
• (n) 3,3′-dichlorobenzophenone
• (o) 4,4′-dichlorobenzophenone
• (p) 2,2'-dichloro-4,4'-dimethoxybenzophenone
• (q) 2,4-dichloro-4'-trifluoromethylbenzophenone
• (r) 2,2'-difluorobenzophenone
• (s) 3,3'-difluorobenzophenone
• (t) 2,2'-dimethoxybenzophenone
• (u) 2,2'-dimethoxy-3,3'-dimethylbenzophenone
• (v) 2,2'-dimethoxy-5,5'-dimethylbenzophenone
• (w) 2,4-dimethoxy-2'-trifluoromethylbenzophenone
• (x) 2,4-dimethoxy-4'-trifluoromethylbenzophenone
• (y) 2,4'-dimethoxy-2,4,6-trimethylbenzophenone
• (z) 2,2'-dimethylbenzophenone
• (aa) 3,3'-dimethylbenzophenone
• (bb) 4,4'-dimethylbenzophenone
• (cc) 4'-fluoro-2,4-dimethoxybenzophenone
• (dd) 4,4'-bis (trifluoromethyl) benzophenone
• (ee) 4'-chloro-2,4,6-trimethylbenzophenone
• (ff) 4,4′-dibromobenzophenone
• (gg) 2,2'-dibromo-4,4'-dimethoxybenzophenone
• (hh) 2-chloro-4,4'-dimethoxybenzophenone or
• (ii) 2,2′-dichlorobenzophenones,
• with the following connections:
• (a) Trans- (4R, 6S) -6- [4,4-bis (2,4-dimethoxyphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (b) Trans- (4R, 6S) -6- [4,4-bis (3,4-dimethoxyphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (c) Trans- (4R, 6S) -6- [4,4-bis (2,4-dimethylphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (d) Trans- (4R, 6S) -6- [4,4-bis (3,4-dimethylphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (e) Trans- (4R, 6S) -6- [4,4-bis (3,5-dimethylphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (f) Trans- (4R, 6S) -6- [4- (4-fluorophenyl) -4- (2,4,6-trimethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (g) Trans- (4R, 6S) -6- [4,4-bis (2,3,4-trimethoxyphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (h) Trans- (4R, 6S) -6- [4,4-bis (2,4,6-trimethylphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (i) Trans- (4R, 6S) -6- [4- (4-methoxyphenyl) -4- (2,5-dimethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (j) Trans- (4R, 6S) -6- [4- (4-methoxyphenyl) -4- (2,4,6-trimethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (k) Trans- (4R, 6S) -6- [4,4-bis (2,4-dichlorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (k) Trans- (4R, 6S) -6- [4,4-bis (2,5-dichlorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (l) Trans- (4R, 6S) -6- [4,4-bis (2,6-dichlorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (m) Trans- (4R, 6S) -6- [4,4-bis (3-chlorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (n) Trans- (4R, 6S) -6- [4,4-bis (4-chlorophenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (o) Trans- (4R, 6S) -6- [4,4-bis (2-chloro-4-methoxyphenyl) -3- (1- methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4- hydroxy-2H-pyran-2-one,
• (p) Trans- (4R, 6S) -6- [4- (2,4-dichlorophenyl) -4- (4-trifluoro methylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-buta dienyl] tetrahydro-4-hydroxy-2H-pyran-2-one,
• (q) Trans- (4R, 6S) -6- [4,4-bis (2-fluorophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (r) Trans- (4R, 6S) -6- [4,4-bis (3-fluorophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (s) Trans- (4R, 6S) -6- [4,4-bis (2-methoxyphenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (t) Trans- (4R, 6S) -6- [4,4-bis (2-methoxy-3-methylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro- 4-hydroxy-2H-pyran-2-one,
• (u) Trans- (4R, 6S) -6- [4,4-bis (2-methoxy-5-methylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro- 4-hydroxy-2H-pyran-2-one,
• (v) Trans- (4R, 6S) -6- [4- (2,4-dimethoxy-4- (2-trifluoromethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (w) Trans- (4R, 6S) -6- [4- (2,4-dimethoxy-4- (4-trifluoromethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (x) Trans- (4R, 6S) -6- [4- (2,4-dimethoxy-4- (2,4,6-trimethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (z) Trans- (4R, 6S) -6- [4,4-bis (2-methylphenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (aa) Trans- (4R, 6S) -6- [4,4-bis (3-methylphenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (bb) Trans- (4R, 6S) -6- [4,4-bis (4-methylphenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (cc) Trans- (4R, 6S) -6- [4- (4-fluorophenyl) -4- (2,4-dimethoxy phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (dd) Trans- (4R, 6S) -6- [4,4-bis (4-trifluoromethylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro- 4-hydroxy-2H-pyran-2-one,
• (ee) Trans- (4R, 6S) -6- [4- (4-chlorophenyl) -4- (2,4,6-trimethyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one,
• (ff) Trans- (4R, 6S) -6- [4,4-bis (4-bromophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one,
• (gg) Trans- (4R, 6S) -6- [4,4-bis (2-bromo-4-methoxyphenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro- 4-hydroxy-2H-pyran-2-one,
• (hh) Trans- (4R, 6S) -6- [4- (2-chloro-4-methoxyphenyl) -4- (4- methoxyphenyl-3- (1-methyl-1H-tetrazol-5-yl) -1,3- butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one, and
• (ii) Trans- (4R, 6S) -6- [4,4-bis (2-chlorophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro- 4-hydroxy-2H-pyran-2-one.

Example 147 Methyl-N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8-nonadien-1-yl] -L- leucinate

If a solution of trans- (4R, 6S) -6- [4,4-bis (4-fluor phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one in tetrahydrofuran with at least one equivalent of L-leucine methyl ester (herge represents treated in situ from the hydrochloride salt) and up to Reflux temperature is heated, so the Title connection established.

Example 148

The general procedure of Example 147 or Bei game 1 of US-PS 46 78 806 is repeated with the Exception that the L-leucine methyl ester used in it is replaced by an equimolar amount of

• (a) L-serine methyl ester,
• (b) L-phenylalanine methyl ester or
• (c) L-tyrosine methyl ester,

with the following connections:

• (a) methyl N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) - dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8- nonadien-1-yl] -L-serinate,
• (b) methyl N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) - dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8- nonadien-1-yl] -L-phenylalaninate and
• (c) methyl N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) - dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8- nonadien-1-yl] -L tyrosinate.

Example 149 N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -1-oxo-6,8-nonadien-1-yl] -L-leucine

If a solution of the compound of Example 147 in Dioxane-water at a temperature of approx. 0 ° C with 1 N NaOH is treated and acidified after working up then the title connection is established.

Example 150

The general procedure of Example 149 or Bei game 2 in US Pat. No. 4,678,806 is repeated with the Except that the compound of Example 147, which is there is used, is replaced by the connections of Example 148, which produces:

• (a) N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8-nonadien-1- yl] -L-serine,
• (b) N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8-nonadien-1- yl] -L-phenylalanine and
• (c) N- [9,9-bis (4-fluorophenyl) -3 (R), 5 (S) -dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -1-oxo-6,8-nonadien-1- yl] -L-tyrosine.

Claims (86)

1. Compounds of the general formula (I): wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; tetfür stands for n is an integer from 0 to 2 inclusive, for stands; R⁷ represents a hydrogen atom, a C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl group; X is -OH or = O; and R⁸ represents a hydrogen atom, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt. 2. Compounds according to claim 1 of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy group; n represents an integer from 0 to 2 inclusive, Afür stands; R⁷ represents a hydrogen atom, a C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl group; X is -OH or = O; and R⁸ represents a hydrogen atom, a hydrolyzable ester group or a cation to form a non-toxic pharmaceutically acceptable salt. 3. Compounds according to claim 2, wherein n is 1. 4. Compounds according to claim 3 of the general formula: wherein
R¹, R²,
R³, R⁴, R⁵
and R⁶ each independently represent a hydrogen, fluorine or chlorine atom, a methyl or methoxy group; For R, is a hydrogen atom or a C _1-4 alkyl group and R⁸ is a hydrogen atom, a C _1-4 alkyl group or a cation to form a non-toxic pharmaceutically acceptable salt. 5. A compound according to claim 1 which is ethyl erythro-9,9-bis (4- fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole- 5-yl) -6,8-nonadienoate. 6. Compound according to claim 1, namely erythro-9,9-bis (4- fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt or hydrate thereof. 7. A compound according to claim 6, namely the (3R, 5S) enantiomer from 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non- toxic pharmaceutically acceptable salt or hydrate from that. 8. The compound of claim 6, namely erythro-9,9-bis (4- fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) - 6,8-nonadienecarboxylic acid monohydrate. 9. Connection according to claim 8, namely the (3R, 5S) - Enatiomer of 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid mono hydrate. 10. A compound according to claim 6, namely sodium erythro 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H- tetrazol-5-yl) -6,8-nonadienoate. 11. Connection according to claim 10, namely the (3R, 5S) - Enantiomer of sodium 9,9-bis (4-fluorophenyl) -3,5- dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate. 12. A compound according to claim 6, namely potassium erythro 9,9-bis (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H- tetrazol-5-yl) -6,8-nonadienoate. 13. Connection according to claim 12, namely the (3R, 5S) - Enantiomer of potassium 9,9-bis (4-fluorophenyl) -3,5-di hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienoate. 14. A compound according to claim 1 which is trans-6- [4,4-bis- (4-fluorophenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3- butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one. 15. A compound according to claim 14, namely the (4R, 6S) - Enantiomer of 6- [4,4-bis- (4-fluorophenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one. 16. The compound of claim 1, namely erythro-11,11-bis- (4-fluorophenyl) -3,5-dihydroxy-10- (1-methyl-1H-tetrazole- 5-yl) -6,8,10-undecatrienecarboxylic acid or not toxic pharmaceutically acceptable salt thereof. 17. A compound according to claim 1 which is trans-6- [4,4-bis- (4-fluorophenyl) -3- (2-methyl-2H-tetrazol-5-yl) -1,3- butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one. 18. The compound according to claim 1, namely erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (2-methyl-2H-tetrazole- 5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt thereof. 19. The compound of claim 1 which is 9,9-bis- (4-fluorine phenyl) -3-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -5-oxo- 6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt thereof. 20. The compound of claim 1, namely erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- [1- (1-methylethyl) -1H- tetrazol-5-yl] -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt thereof. 21. A compound according to claim 1 which is ethyl erythro-9.9. bis- (4-fluorophenyl) -3-hydroxy-8- [1- (1-methylethyl) - 1H-tetrazol-5-yl] -6-8 nonadienoate. 22. A compound according to claim 1, namely erythro-9,9-bis- (4-fluoro-3-methylphenyl) -3,5-dihydroxy-8- (1-methyl-1H- tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non- toxic pharmaceutically acceptable salt thereof. 23. A compound according to claim 1, namely trans-6- [4,4-bis- (4-fluoro-3-methylphenyl) -3- (1-methyl-1H-tetrazol-5-yl) - 1,3-butadienyl] tetrahydro-4-hydroxy-2H-pyran-2-one. 24. The compound according to claim 1, namely erythro-9,9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazole-5- yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt thereof. 25. A compound according to claim 1, namely erythro-9,9-bis- (2,4-dimethylphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt from that. 26. The compound of claim 1, namely erythro-9-9-bis- (4-fluorophenyl) -3,5-dihydroxy-8- [1- (2- methoxyethoxy-methyl-1H-tetrazol-5-yl] -6,8-nonadiene carboxylic acid or a non-toxic pharmaceutical tolerable salt of it. 27. A compound according to claim 1, namely erythro-9,9-bis- (4-fluoro-2-methylphenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable Salt of it. 28. The compound of claim 27, namely (3R, 5S) enantiomer of 9,9-bis (4-fluoro-2-methylphenyl) - 3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nona diencarboxylic acid or a non-toxic pharmaceutical tolerable salt of it. 29. A compound according to claim 1, namely trans-6- [4,4-bis- (4-fluoro-2-methylphenyl) -3- (1-methyl- 1H-tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one. 30. The compound of claim 29, namely (4R, 6S) enantiomer of 6- [4,4-bis- (4-fluoro-2-methyl phenyl) -3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] - tetrahydro-4-hydroxy-2H-pyran-2-one. 31. A compound according to claim 1, namely erythro-9,9-bis- (4-fluoro-4-methylphenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable Salt of it. 32. The compound of claim 1, namely erythro-9- (4-fluorophenyl) -3,5-dihydroxy-8- (1-methyl-1H- tetrazol-5-yl) -9-phenylnona-6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt from that. 33. Connection according to claim 32, namely that (3R, 5S) enantiomer of 9- (4-fluorophenyl) -3,5-dihydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -9-phenylnona-6,8-diene carboxylic acid or a non-toxic pharmaceutical tolerable salt of it. 34. The compound of claim 1, namely trans-6- [4- (4-fluorophenyl) -4-phenyl-3- (1-methyl-1H- tetrazol-5-yl) -1,3-butadienyl] tetrahydro-4-hydroxy- 2H-pyran-2-one. 35. Connection according to claim 34, namely that (4R, 6S) enantiomer of 6- [4- (4-fluorophenyl) -4-phenyl- 3- (1-methyl-1H-tetrazol-5-yl) -1,3-butadienyl] tetra hydro-4-hydroxy-2H-pyran-2-one. 36. The compound of claim 1, namely erythro-9,9-diphenyl-3,5-dihydroxy-8- (1-methyl-1H-tetra zol-5-yl) -6,8-nonadienecarboxylic acid or not toxic pharmaceutically acceptable salt thereof. 37. The compound of claim 1, namely erythro-9,9-bis- (4-methoxyphenyl) -3,5-dihydroxy-8- (1-methyl-1H-tetrazol-5-yl) -6,8-nonadienecarboxylic acid or a non-toxic pharmaceutically acceptable salt from that. 38. Compounds of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; tetfür is n is an integer from 0 to 2 inclusive, R⁷ is a C _1-4 alkyl, C _1-4 alkoxy lower alkyl, (2-methoxyethoxy) methyl or triphenylmethyl group; R⁹ means a hydrolyzable ester group. 39. Compounds according to claim 38 of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; n represents an integer from 0 to 2 inclusive, R⁷ represents a C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl group; and R⁹ represents a hydrolyzable ester group. 40. Compounds according to claim 39, wherein n is 1. 41. Compounds according to claim 40, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are each selected from hydrogen, fluorine, chlorine, methyl and methoxy; and R⁷ represents a C _1-4 alkyl group. 42. The compound of claim 38, namely Ethyl 9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 43. The compound of claim 42, namely Ethyl- (5S) -9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 44. The compound of claim 38, namely tert-butyl-9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 45. The compound of claim 44, namely tert-butyl- (5S) -9,9-bis (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 46. The compound of claim 38, namely Ethyl-9,9-bis (4-fluoro-3-methylphenyl) -5-hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 47. The compound of claim 38, namely Ethyl 9,9-bis (2,4-dimethylphenyl) -5-hydroxy-8- (1- methyl 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 48. The compound of claim 38, namely tert-butyl-9,9-bis (4-fluoro-2-methylphenyl) -5-hydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 49. The compound of claim 48, namely tert-butyl- (5S) -9,9-bis (4-fluoro-2-methylphenyl) -5- hydroxy-8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nona dienoat. 50. The compound of claim 38, namely tert-butyl-9,9-bis (2-fluoro-4-methylphenyl) -5-hydroxy- 8- (1-methyl-1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 51. The compound of claim 38, namely Ethyl 9- (4-fluorophenyl) -5-hydroxy-8- (1-methyl-1H-tetra zol-5-yl) -9-phenyl-3-oxo-6,8-nonadienoate. 52. The compound of claim 38, namely Methyl 9,9-diphenyl-5-hydroxy-8- (1-methyl-1H-tetrazole- 5-yl) -3-oxo-6,8-nonadienoate. 53. The compound of claim 38, namely Ethyl 9,9-bis (4-methoxyphenyl) -5-hydroxy-8- (1-methyl- 1H-tetrazol-5-yl) -3-oxo-6,8-nonadienoate. 54. Compounds of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; tetfür is n is an integer from 0 to 2 inclusive, R⁷eine C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl or triphenylmethyl group 55. Compound according to claim 54 of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; n represents an integer from 0 to 2 inclusive, R⁷eine C _1-4 alkyl, C _1-4 alkoxy lower alkyl or (2-methoxyethoxy) methyl group. 56. Compounds according to claim 55, wherein n is 0. 57. Compounds according to claim 55, wherein n is 1. 58. Compounds according to claim 56, wherein R⁷ is methyl group means. 59. Compounds according to claim 57, wherein R⁷ is methyl group means. 60. Compounds according to claim 58, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are each selected from hydrogen, chlorine, Fluorine, methyl and methoxy. 61. Compounds according to claim 59, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are each selected from hydrogen, chlorine, Fluorine, methyl and methoxy. 62. The compound of claim 54, namely 3,3-bis- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) - propenal. 63. The compound of claim 54, namely 5,5-bis- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) - 2,4-pentadienal. 64. The compound of claim 54, namely 3,3-bis- (4-fluoro-3-methylphenyl) -2- (1-methyl-1H-tetrazole- 5-yl) propenal. 65. The compound of claim 54, namely 5,5-bis- (4-fluoro-3-methylphenyl) -4- (1-methyl-1H-tetra zol-5-yl) -2,4-pentadienal. 66. The compound of claim 54, namely 3,3-bis- (2,4-dimethylphenyl) -2- (1-methyl-1H-tetrazole- 5-yl) propenal. 67. The compound of claim 54, namely 5,5-bis- (2,4-dimethylphenyl) -4- (1-methyl-1H-tetra zol-5-yl) -2,4-pentadienal. 68. The compound of claim 54, namely 3,3-bis- (4-fluoro-2-methylphenyl) -2- (1-methyl-1H-tetrazole- 5-yl) propenal. 69. The compound of claim 54, namely 5,5-bis- (4-fluoro-2-methylphenyl) -4- (1-methyl-1H-tetra zol-5-yl) -2,4-pentadienal. 70. The compound of claim 54, namely 3,3-bis- (2-fluoro-4-methylphenyl) -2- (1-methyl-1H- tetrazol-5-yl) propenal. 71. The compound of claim 54, namely 5,5-bis- (2-fluoro-4-methylphenyl) -4- (1-methyl-1H-tetra zol-5-yl) -2,4-pentadienal. 72. The compound of claim 54, namely 3,3-bis- (4-fluorophenyl) -2- [2- (triphenylmethyl) -2H- tetrazol-5-yl] propenal. 73. The compound of claim 54, namely 5,5-bis- (4-fluorophenyl) -4- [2- (triphenylmethyl) -2H- tetrazol-5-yl] -2,4-pentadienal. 74. The compound of claim 54, namely 3- (4-fluorophenyl) -2- (1-methyl-1H-tetrazol-5-yl) -3- phenylpropenal. 75. The compound of claim 54, namely 5- (4-fluorophenyl) -4- (1-methyl-1H-tetrazol-5-yl) -5- phenyl-2,4-pentadienal. 76. The compound of claim 54, namely 3,3-diphenyl-2- (1-methyl-1H-tetrazol-5-yl) propenal. 77. The compound of claim 54, namely 5,5-diphenyl-4- (1-methyl-1H-tetrazol-5-yl) -2,4-penta dienal. 78. The compound of claim 54, namely 3,3-bis- (4-methoxyphenyl) -2- (1-methyl-1H-tetrazole- 5-yl) propenal. 79. The compound of claim 54, namely 5,5-bis- (4-methoxyphenyl) -4- (1-methyl-1H-tetra zol-5-yl) -2,4-pentadienal. 80. Compounds of the general formula: wherein
R¹ and R⁴ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl group; R², R³,
R⁵ and R⁶ each independently represent a hydrogen or halogen atom, a C _1-4 alkyl or C _1-4 alkoxy group; R²⁰ represents a hydrogen atom, a C _1-6 alkyl group or a metal cation; and R²¹ is a C _1-6 -alkyl-, hydroxy-C _1-6 -alkyl-, phenyl-C _1-6 -alkyl-, hydroxyphenyl-C _1-6 -alkyl-, amido-C _1-6 -alkyl-, C _1-6 alkoxycarbonyl-C _1-6 alkyl, imidazol-4-yl-C _1-6 alkyl, C _1-6 - alkylthio-C _1-6 alkyl or indol-3-yl C _1-6 alkyl group, the amido ester unit having the L configuration. 81. Compounds according to claim 80, wherein R²⁰ is a hydrogen atom, a C _1-2 alkyl group or a metal cation and R²¹ is a C _1-4 alkyl, hydroxy-C _1-2 alkyl, phenyl C _1-2 - alkyl, hydroxyphenyl C _1-2 alkyl, amido C _1-2 alkyl, C _1-2 alkoxycarbonyl C _1-2 alkyl, imidazol-4-yl C _1-2 alkyl -, C _1-2 alkylthio-C _1-2 alkyl or indol-3-yl C _1-2 alkyl group, the amido ester unit having the L configuration. 82. Compounds according to claim 81, wherein R²¹ represents a C _1-4 alkyl, hydroxymethyl, phenylmethyl or hydroxyphenylmethyl group, the amido ester unit having the L configuration. 83. Compounds of claims 1 to 37 and 80 to 82 for pharmaceutical application. 84. Pharmaceutical composition containing at least one A compound according to any one of claims 1 to 37 and 80 to 82, optionally together with conventional pharmaceutical Carriers and / or auxiliaries. 85. Use of a compound according to any one of the claims 1 to 37 and 80 to 82 for treatment or contraception of hypercholesterolemia, hyperlipoproteinemia or Arteriosclerosis. 86. Process for the preparation of the compounds of formula I according to one of claims 1 to 37, characterized in that

• a) a compound of the general formula IIa or IIb: wherein R¹ to R⁷ have the meanings given in claim 1, with one or two equivalents of triphenylphosphoranylidene acetaldehyde to give a compound of the general formula: in which R¹ to R⁷ and n have the meanings given in Claim 1,
• b) the starting or the end products from step (a) with the dianion of the acetoacetate ester to give a compound of the general formula: or in which R¹ to R⁷ and have the meanings given in Claim 1 and R⁹ denotes a hydrolyzable ester group,
• c) the ketone ester from step (b) is reduced by reacting it with a trisubstituted alkyl borane, then with sodium borohydride and finally with methanol, and
• d) the ester radical R⁹ is cleaved by basic hydrolysis in an organic solvent, giving a compound of the formula I in which R⁹ is O ^- M⁺, where M⁺ is a cation,
• e) acidifying the product obtained from step (d), giving a compound of formula I in which R⁹ is a hydrogen atom, and
• f) the product from step (e) is cyclized by activating the carboxyl radical with a carbodiimide in an inert organic solvent to give a compound of the formula I in which A is a lactone.